Functional genomic approaches to elucidate the role of enhancers during development

Advanced Review

Genevieve E. Ryan, Emma K. Farley

Published Online: Dec 05 2019

DOI: 10.1002/wsbm.1467

Full article on Wiley Online Library: HTML PDF

Can't access this content? Tell your librarian.

Abstract Successful development depends on the precise tissue‐specific regulation of genes by enhancers, genetic elements that act as switches to control when and where genes are expressed. Because enhancers are critical for development, and the majority of disease‐associated mutations reside within enhancers, it is essential to understand which sequences within enhancers are important for function. Advances in sequencing technology have enabled the rapid generation of genomic data that predict putative active enhancers, but functionally validating these sequences at scale remains a fundamental challenge. Herein, we discuss the power of genome‐wide strategies used to identify candidate enhancers, and also highlight limitations and misconceptions that have arisen from these data. We discuss the use of massively parallel reporter assays to test enhancers for function at scale. We also review recent advances in our ability to study gene regulation during development, including CRISPR‐based tools to manipulate genomes and single‐cell transcriptomics to finely map gene expression. Finally, we look ahead to a synthesis of complementary genomic approaches that will advance our understanding of enhancer function during development. This article is categorized under: Physiology > Mammalian Physiology in Health and Disease Developmental Biology > Developmental Processes in Health and Disease Laboratory Methods and Technologies > Genetic/Genomic Methods

Genome‐wide methods to identify putative enhancers. The basic principle of each experimental approach and the corresponding data readout is shown for each method. (a) Chromatin immunoprecipitation followed by high‐throughput sequencing (ChIP‐seq) uses antibodies targeting a specific TF to determine the location of its binding sites genome‐wide. The broad peaks generated by ChIP‐seq cannot determine precise footprints of TF binding, but this can be achieved by adding a 5′ to 3′ exonuclease digestion step to the protocol (ChIP‐exo). (b) Nucleosomes flanking active enhancers often carry stereotypical histone modifications (e.g., H3K4me1 and H3K27ac) that can be detected with specific antibodies by ChIP‐seq. (c) Active enhancers and other cis‐regulatory elements are found within open chromatin that is depleted of nucleosomes. Accessible chromatin can be detected by DNase I digestion followed by high‐throughput sequencing (DNase‐seq). (d) Accessible chromatin can also be detected by assay for transposase‐accessible chromatin using sequencing (ATAC‐seq), where Tn5 transposase simultaneously fragments and tags accessible DNA prior to sequencing

[ Normal View | Magnified View ]

scRNA methodologies to build atlases of animal development. Single cell RNA‐sequencing (scRNA‐seq) methods used to generate atlases of animal development are illustrated using Drosophila as a model system. Staged embryos are collected and dissociated before being subjected to (a) droplet‐based scRNA‐seq or (b) single‐cell combinatorial indexing RNA‐seq (sciRNA‐seq). Droplet‐based scRNA‐seq methods utilize beads bearing primers that contain two unique barcodes, one that is cell‐specific and one that is transcript‐specific (Unique Molecular Identifier). The primers also contain a PCR handle for subsequent amplification. For sciRNA‐seq, cells are distributed to multiwell plates where they receive a well‐specific barcode during reverse transcription. Cells are then pooled and distributed to new multiwell plates where they receive a second well‐specific barcode during amplification. A third level of indexing can increase the number of cells processed in a single experiment (not shown). (c) Single‐cell transcriptomic data is represented as a t‐distributed stochastic neighbor embedding (t‐SNE) or uniform manifold approximation and projection (UMAP) plot, which cluster cells based on the similarity of their transcriptomes. (d) Cell type‐specific markers and in situ hybridization data can be used to map single‐cell transcriptomes back to a virtual embryo

[ Normal View | Magnified View ]

CRISPR‐based methods to identify and study candidate enhancers. (a) Any genomic region containing a protospacer‐adjacent motif (PAM) can be targeted by CRISPR/Cas9. (b) The workflow for high‐throughput CRISPR screens includes building a library of sgRNAs, cloning the library into lentiviral vectors, infecting cells that stably express Cas9 or one of its variant forms, and phenotyping cells. The sgRNA(s) carried by cells of a given phenotype can easily be identified by sequencing, and can give insight into candidate cis‐regulatory regions that affect phenotype. CRISPR screens can utilize (c) one sgRNA to mutate a particular locus, or (d) two sgRNAs to delete a genomic region. In both cases, DNA cut by Cas9 will be repaired by the error‐prone non‐homologous end joining (NHEJ) pathway, creating indels. Variant forms of Cas9 that are used in high‐throughput screens include (e) CRISPRa to activate transcription and (f) CRISPRi to repress transcription. Both CRISPRa and CRISPRi utilize catalytically dead Cas9 fused to an effector protein and impact gene expression through chromatin remodeling. Figure created with BioRender

[ Normal View | Magnified View ]

In vivo massively parallel reporter assays to study enhancer function. (a) Enhancer‐FACS‐seq identifies active, tissue‐specific enhancers in whole Drosophila embryos. Two flies are crossed, the first carrying a candidate enhancer sequence driving GFP expression, and the second expressing a cell surface marker in a tissue‐specific manner. Embryos resulting from this cross are dissociated and FACS sorted for the tissue‐specific cell surface marker and GFP. Genomic DNA can then be extracted from sorted cells to identify enhancers that are active in the specific tissue. (b) Synthetic enhancer library‐sequencing (SEL‐seq) allows millions of enhancer variants to be tested for function in whole Ciona embryos. Synthetic enhancer variants are attached to a minimal promoter, GFP coding sequence, and a unique transcribable barcode. The enhancer library is electroporated into hundreds of thousands of fertilized Ciona eggs, which are then allowed to develop until the desired developmental stage. Barcode‐tagged mRNA can then be isolated and sequenced to identify active enhancer variants, providing insight into which sequences within an enhancer are important for function. Figure created with BioRender

[ Normal View | Magnified View ]

In vitro massively parallel reporter assays (MPRAs) to study enhancer function. MPRAs utilize advances in oligonucleotide synthesis and sequencing technology to test large libraries of candidate enhancer sequences for function. (a) MPRA libraries typically contain candidate enhancer sequences upstream of a minimal promoter and reporter gene. A transcribable barcode unique to each candidate enhancer is placed in the 3′ untranslated region of the reporter gene, allowing active enhancers to be identified by sequencing barcode‐tagged mRNAs. (b) Self‐transcribing active regulatory region sequencing (STARR‐seq) is a variation of the MPRA that exploits the characteristic that enhancers can function independently of their relative positions. In STARR‐seq, candidate enhancer sequences are placed downstream of a minimal promoter and reporter gene, allowing active enhancers to transcribe themselves. Figure created with BioRender

[ Normal View | Magnified View ]

Genome‐wide methods to identify putative enhancer–promoter interactions. Distal enhancers (shown in pink) may be brought within close proximity to the promoters they regulate (shown in black) through the formation of chromatin loops. Looping is facilitated by protein–protein interactions of transcription factors that assemble at promoters and enhancers. The basic principles of methods to detect chromatin interactions are shown. Both (a) chromatin conformation capture (3C)‐based methods, including Hi‐C, and (b) chromatin interaction analysis with paired‐end tag sequencing (ChIA‐PET) preserve and detect chromatin interactions through crosslinking, fragmentation, and proximity ligation followed by high‐throughput sequencing. ChIA‐PET includes a chromatin immunoprecipitation step, often using antibodies targeting RNA pol II (shown), to enrich for complexes containing promoters. (c) Genome architecture mapping captures the distance between genomic loci by cryosectioning and laser microdissection (which allow spatial information to be preserved) followed by DNA sequencing

[ Normal View | Magnified View ]

References

Adey,, A., Morrison,, H. G., Asan,, Xun,, X., Kitzman,, J. O., Turner,, E. H., … Shendure,, J. (2010). Rapid, low‐input, low‐bias construction of shotgun fragment libraries by high‐density in vitro transposition. Genome Biology, 11(12), R119. https://doi.org/10.1186/gb-2010-11-12-r119
Afek,, A., Schipper,, J. L., Horton,, J., Gordân,, R., & Lukatsky,, D. B. (2014). Protein−DNA binding in the absence of specific base‐pair recognition. Proceedings of the National Academy of Sciences, 111(48), 17140–17145. https://doi.org/10.1073/pnas.1410569111
Amano,, T., Sagai,, T., Tanabe,, H., Mizushina,, Y., Nakazawa,, H., & Shiroishi,, T. (2009). Chromosomal dynamics at the Shh locus: Limb bud‐specific differential regulation of competence and active transcription. Developmental Cell, 16(1), 47–57. https://doi.org/10.1016/j.devcel.2008.11.011
Arnold,, C. D., Gerlach,, D., Stelzer,, C., Boryń,, Ł. M., Rath,, M., & Stark,, A. (2013). Genome‐wide quantitative enhancer activity maps identified by STARR‐seq. Science, 339(6123), 1074–1077. https://doi.org/10.1126/science.1232542
Banani,, S. F., Lee,, H. O., Hyman,, A. A., & Rosen,, M. K. (2017). Biomolecular condensates: Organizers of cellular biochemistry. Nature Reviews Molecular Cell Biology, 18(5), 285–298. https://doi.org/10.1038/nrm.2017.7
Banerji,, J., Rusconi,, S., & Schaffner,, W. (1981). Expression of a β‐globin gene is enhanced by remote SV40 DNA sequences. Cell, 27, 299–308. https://doi.org/10.1016/0092-8674(81)90413-X
Barski,, A., Cuddapah,, S., Cui,, K., Roh,, T. Y., Schones,, D. E., Wang,, Z., … Zhao,, K. (2007). High‐resolution profiling of histone methylations in the human genome. Cell, 129, 823–837. https://doi.org/10.1016/j.cell.2007.05.009
Beagrie,, R. A., Scialdone,, A., Schueler,, M., Kraemer,, D. C. A., Chotalia,, M., Xie,, S. Q., … Pombo,, A. (2017). Complex multi‐enhancer contacts captured by genome architecture mapping. Nature, 543(7646), 519–524. https://doi.org/10.1038/nature21411
Becht,, E., McInnes,, L., Healy,, J., Dutertre,, C. A., Kwok,, I. W. H., Ng,, L. G., … Newell,, E. W. (2019). Dimensionality reduction for visualizing single‐cell data using UMAP. Nature Biotechnology, 37(1), 38–47. https://doi.org/10.1038/nbt.4314
Beerli,, R. R., Dreier,, B., & Barbas,, C. F. (2000). Positive and negative regulation of endogenous genes by designed transcription factors. Proceedings of the National Academy of Sciences, 97(4), 1495–1500. https://doi.org/10.1073/pnas.040552697
Benabdallah,, N. S., Williamson,, I., Illingworth,, R. S., Boyle,, S., Grimes,, G. R., Therizols,, P., & Bickmore,, W. (2017). PARP mediated chromatin unfolding is coupled to long‐range enhancer activation. BioRxiv. https://doi.org/10.1101/155325
Bernstein,, B. E., Mikkelsen,, T. S., Xie,, X., Kamal,, M., Huebert,, D. J., Cuff,, J., … Lander,, E. S. (2006). A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell, 125, 315–326. https://doi.org/10.1016/j.cell.2006.02.041
Bertrand,, V., Hudson,, C., Caillol,, D., Popovici,, C., & Lemaire,, P. (2003). Neural tissue in ascidian embryos is induced by FGF9/16/20, acting via a combination of maternal GATA and Ets transcription factors. Cell, 115(5), 615–627. https://doi.org/10.1016/S0092-8674(03)00928-0
Birnbaum,, R. Y., Patwardhan,, R. P., Kim,, M. J., Findlay,, G. M., Martin,, B., Zhao,, J., … Ahituv,, N. (2014). Systematic dissection of coding exons at single nucleotide resolution supports an additional role in cell‐specific transcriptional regulation. PLoS Genetics, 10(10), e1004592. https://doi.org/10.1371/journal.pgen.1004592
Blinka,, S., Reimer,, M. H., Pulakanti,, K., & Rao,, S. (2016). Super‐enhancers at the Nanog locus differentially regulate neighboring pluripotency‐associated genes. Cell Reports, 17, 19–28. https://doi.org/10.1016/j.celrep.2016.09.002
Blow,, M. J., McCulley,, D. J., Li,, Z., Zhang,, T., Akiyama,, J. A., Holt,, A., … Pennacchio,, L. A. (2010). ChIP‐seq identification of weakly conserved heart enhancers. Nature Genetics, 42(9), 806–810. https://doi.org/10.1038/ng.650
Boija,, A., Klein,, I. A., Sabari,, B. R., Dall`Agnese,, A., Coffey,, E. L., Zamudio,, A. V., … Young,, R. A. (2018). Transcription factors activate genes through the phase‐separation capacity of their activation domains. Cell, 175(7), 1842–1855.e16. https://doi.org/10.1016/j.cell.2018.10.042
Bonn,, S., Zinzen,, R. P., Girardot,, C., Gustafson,, E. H., Perez‐Gonzalez,, A., Delhomme,, N., … Furlong,, E. E. M. (2012). Tissue‐specific analysis of chromatin state identifies temporal signatures of enhancer activity during embryonic development. Nature Genetics, 44, 148–156. https://doi.org/10.1038/ng.1064
Boyle,, A. P., Davis,, S., Shulha,, H. P., Meltzer,, P., Margulies,, E. H., Weng,, Z., … Crawford,, G. E. (2008). High‐resolution mapping and characterization of open chromatin across the genome. Cell, 132(2), 311–322. https://doi.org/10.1016/j.cell.2007.12.014
Briggs,, J. A., Weinreb,, C., Wagner,, D. E., Megason,, S., Peshkin,, L., Kirschner,, M. W., & Klein,, A. M. (2018). The dynamics of gene expression in vertebrate embryogenesis at single‐cell resolution. Science, 360(6392), eaar5780. https://doi.org/10.1126/science.aar5780
Bubeck,, F., Hoffmann,, M. D., Harteveld,, Z., Aschenbrenner,, S., Bietz,, A., Waldhauer,, M. C., … Niopek,, D. (2018). Engineered anti‐CRISPR proteins for optogenetic control of CRISPR‐Cas9. Nature Methods, 15(11), 924–927. https://doi.org/10.1038/s41592-018-0178-9
Buenrostro,, J. D., Giresi,, P. G., Zaba,, L. C., Chang,, H. Y., & Greenleaf,, W. J. (2013). Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA‐binding proteins and nucleosome position. Nature Methods, 10(12), 1213–1218. https://doi.org/10.1038/nmeth.2688
Buenrostro,, J. D., Wu,, B., Litzenburger,, U. M., Ruff,, D., Gonzales,, M. L., Snyder,, M. P., … Greenleaf,, W. J. (2015). Single‐cell chromatin accessibility reveals principles of regulatory variation. Nature, 523(7561), 486–490. https://doi.org/10.1038/nature14590
Burgio,, G. (2018). Redefining mouse transgenesis with CRISPR/Cas9 genome editing technology. Genome Biology, 19(1), 18–20. https://doi.org/10.1186/s13059-018-1409-1
Calhoun,, V. C., Stathopoulos,, A., & Levine,, M. (2002). Promoter‐proximal tethering elements regulate enhancer‐promoter specificity in the Drosophila Antennapedia complex. Proceedings of the National Academy of Sciences of the United States of America, 99(14), 9243–9247. https://doi.org/10.1073/pnas.142291299
Canver,, M. C., Smith,, E. C., Sher,, F., Pinello,, L., Sanjana,, N. E., Shalem,, O., … Bauer,, D. E. (2015). BCL11A enhancer dissection by Cas9‐mediated in situ saturating mutagenesis. Nature, 527(7577), 192–197. https://doi.org/10.1038/nature15521
Cao,, C., Lemaire,, L. A., Wang,, W., Yoon,, P. H., Choi,, Y. A., Parsons,, L. R., … Chen,, K. (2019). Comprehensive single‐cell transcriptome lineages of a proto‐vertebrate. Nature, 571, 349–354. https://doi.org/10.1038/s41586-019-1385-y
Cao,, J., Packer,, J. S., Ramani,, V., Cusanovich,, D. A., Huynh,, C., Daza,, R., … Shendure,, J. (2017). Comprehensive single‐cell transcriptional profiling of a multicellular organism. Science, 357, 661. https://doi.org/10.1126/science.aam8940
Cao,, J., Spielmann,, M., Qiu,, X., Huang,, X., Ibrahim,, D. M., Hill,, A. J., … Shendure,, J. (2019). The single‐cell transcriptional landscape of mammalian organogenesis. Nature, 566, 496–502. https://doi.org/10.1038/s41586-019-0969-x
Carter,, D., Chakalova,, L., Osborne,, C. S., Dai,, Y. f., & Fraser,, P. (2002). Long‐range chromatin regulatory interactions in vivo. Nature Genetics, 32, 623–626. https://doi.org/10.1038/ng1051
Chen,, K. H., Boettiger,, A. N., Moffitt,, J. R., Wang,, S., & Zhuang,, X. (2015). Spatially resolved, highly multiplexed RNA profiling in single cells. Science, 348(6233), 1360–1363. https://doi.org/10.1126/science.aaa6090
Chen,, S., Sanjana,, N. E., Zheng,, K., Shalem,, O., Lee,, K., Shi,, X., … Sharp,, P. A. (2015). Genome‐wide CRISPR screen in a mouse model of tumor growth and metastasis. Cell, 160(6), 1246–1260. https://doi.org/10.1016/j.cell.2015.02.038
Cho,, W. K., Spille,, J. H., Hecht,, M., Lee,, C., Li,, C., Grube,, V., & Cisse,, I. I. (2018). Mediator and RNA polymerase II clusters associate in transcription‐dependent condensates. Science, 361(6400), 412–415. https://doi.org/10.1126/science.aar4199
Chong,, S., Dugast‐Darzacq,, C., Liu,, Z., Dong,, P., Dailey,, G. M., Cattoglio,, C., … Tjian,, R. (2018). Imaging dynamic and selective low‐complexity domain interactions that control gene transcription. Science, 361(6400), eaar2555. https://doi.org/10.1126/science.aar2555
Cong,, L., Ran,, F. A., Cox,, D., Lin,, S., Barretto,, R., Habib,, N., … Zhang,, F. (2013). Multiplex genome engineering using CRISPR/Cas systems. Science, 339(6121), 819–823. https://doi.org/10.1126/science.1231143
Corradin,, O., & Scacheri,, P. C. (2014). Enhancer variants: Evaluating functions in common disease. Genome Medicine, 6(10), 85. https://doi.org/10.1186/s13073-014-0085-3
Creyghton,, M. P., Jaenisch,, R., Young,, R. A., Kooistra,, T., Lodato,, M. A., Carey,, B. W., … Hanna,, J. (2010). Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proceedings of the National Academy of Sciences, 107(50), 21931–21936. https://doi.org/10.1073/pnas.1016071107
Crocker,, J., Abe,, N., Rinaldi,, L., McGregor,, A. P., Frankel,, N., Wang,, S., … Stern,, D. L. (2015). Low affinity binding site clusters confer HOX specificity and regulatory robustness. Cell, 160, 191–203. https://doi.org/10.1016/j.cell.2014.11.041
Crocker,, J., Preger‐Ben Noon,, E., & Stern,, D. L. (2016). The soft touch: Low‐affinity transcription factor binding sites in development and evolution. Current Topics in Developmental Biology, 117, 455–469. https://doi.org/10.1016/bs.ctdb.2015.11.018
Deans,, R. M., Morgens,, D. W., Ökesli,, A., Pillay,, S., Horlbeck,, M. A., Kampmann,, M., … Bassik,, M. C. (2016). Parallel shRNA and CRISPR‐Cas9 screens enable antiviral drug target identification. Nature Chemical Biology, 12(5), 361–366. https://doi.org/10.1038/nchembio.2050
Dekker,, J., Rippe,, K., Dekker,, M., & Kleckner,, N. (2002). Capturing chromosome conformation. Science, 295(5558), 1306–1311. https://doi.org/10.1126/science.1067799
Delsuc,, F., Brinkmann,, H., Chourrout,, D., & Philippe,, H. (2006). Tunicates and not cephalochordates are the closest living relatives of vertebrates. Nature, 439, 965–968. https://doi.org/10.1038/nature04336
Despang,, A., Schöpflin,, R., Franke,, M., Ali,, S., Jerković,, I., Paliou,, C., … Ibrahim,, D. M. (2019). Functional dissection of the Sox9‐Kcnj2 locus identifies nonessential and instructive roles of TAD architecture. Nature Genetics, 51, 1263–1271. https://doi.org/10.1038/s41588-019-0466-z
DeWitt,, W. S., Shendure,, J., Steemers,, F. J., Regalado,, S. G., Berletch,, J. B., Trapnell,, C., … Cusanovich,, D. A. (2018). A single‐cell atlas of in vivo mammalian chromatin accessibility. Cell, 174(5), 1309–1324.e18. https://doi.org/10.1016/j.cell.2018.06.052
Dixit,, A., Parnas,, O., Li,, B., Chen,, J., Fulco,, C. P., Jerby‐Arnon,, L., … Regev,, A. (2016). Perturb‐Seq: Dissecting molecular circuits with scalable single‐cell RNA profiling of pooled genetic screens. Cell, 167(7), 1853–1866. https://doi.org/10.1016/j.cell.2016.11.038
Dixon,, J. R., Selvaraj,, S., Yue,, F., Kim,, A., Li,, Y., Shen,, Y., … Ren,, B. (2012). Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature, 485(7398), 376–380. https://doi.org/10.1038/nature11082
Dorsett,, D., Gause,, M., Piunti,, A., Takahashi,, Y., Wang,, L., Shilatifard,, A., … Bartom,, E. T. (2017). Histone H3K4 monomethylation catalyzed by Trr and mammalian COMPASS‐like proteins at enhancers is dispensable for development and viability. Nature Genetics, 49(11), 1647–1653. https://doi.org/10.1038/ng.3965
Doyle,, B., Fudenberg,, G., Imakaev,, M., & Mirny,, L. A. (2014). Chromatin loops as allosteric modulators of enhancer‐promoter interactions. PLoS Computational Biology, 10(10), e1003867. https://doi.org/10.1371/journal.pcbi.1003867
Dunham,, I., Kundaje,, A., Aldred,, S. F., Collins,, P. J., Davis,, C. A., Doyle,, F., … Lochovsky,, L. (2012). An integrated encyclopedia of DNA elements in the human genome. Nature, 489, 57–74. https://doi.org/10.1038/nature11247
Erceg,, J., Saunders,, T. E., Girardot,, C., Devos,, D. P., Hufnagel,, L., & Furlong,, E. E. M. (2014). Subtle changes in motif positioning cause tissue‐specific effects on robustness of an enhancer`s activity. PLoS Genetics, 10(1), e1004060. https://doi.org/10.1371/journal.pgen.1004060
Ernst,, J., Kheradpour,, P., Mikkelsen,, T. S., Shoresh,, N., Ward,, L. D., Epstein,, C. B., … Bernstein,, B. E. (2011). Mapping and analysis of chromatin state dynamics in nine human cell types. Nature, 473(7345), 43–49. https://doi.org/10.1038/nature09906
Farley,, E. K., Levine,, M. S., Olson,, K. M., Zhang,, W., & Rokhsar,, D. S. (2016). Syntax compensates for poor binding sites to encode tissue specificity of developmental enhancers. Proceedings of the National Academy of Sciences, 113(23), 6508–6513. https://doi.org/10.1073/pnas.1605085113
Farley,, E. K., Olson,, K. M., & Levine,, M. S. (2016). Regulatory principles governing tissue specificity of developmental enhancers. Cold Spring Harbor Symposia on Quantitative Biology, 80, 27–32. https://doi.org/10.1101/sqb.2015.80.027227
Farley,, E. K., Olson,, K. M., Zhang,, W., Brandt,, A. J., Rokhsar,, D. S., & Levine,, M. S. (2015). Suboptimization of developmental enhancers. Science, 350, 325–328. https://doi.org/10.1126/science.aac6948
Farrell,, J. A., Wang,, Y., Riesenfeld,, S. J., Shekhar,, K., Regev,, A., & Schier,, A. F. (2018). Single‐cell reconstruction of developmental trajectories during zebrafish embryogenesis. Science, 360(6392), eaar3131. https://doi.org/10.1126/science.aar3131
Franke,, M., Ibrahim,, D. M., Andrey,, G., Schwarzer,, W., Heinrich,, V., Schöpflin,, R., … Mundlos,, S. (2016). Formation of new chromatin domains determines pathogenicity of genomic duplications. Nature, 538(7624), 265–269. https://doi.org/10.1038/nature19800
Friedland,, A. E., Tzur,, Y. B., Esvelt,, K. M., Colaiácovo,, M. P., Church,, G. M., & Calarco,, J. A. (2013). Heritable genome editing in C. elegans via a CRISPR‐Cas9 system. Nature Methods, 10(8), 741–743. https://doi.org/10.1038/nmeth.2532
Fulco,, C. P., Munschauer,, M., Anyoha,, R., Munson,, G., Grossman,, S. R., Perez,, E. M., … Engreitz,, J. M. (2016). Systematic mapping of functional enhancer‐promoter connections with CRISPR interference. Science, 354(6313), 769–773. https://doi.org/10.1126/science.aag2445
Fullwood,, M. J., Liu,, M. H., Pan,, Y. F., Liu,, J., Xu,, H., Mohamed,, Y. B., … Ruan,, Y. (2009). An oestrogen‐receptor‐α‐bound human chromatin interactome. Nature, 462(7269), 58–64. https://doi.org/10.1038/nature08497
Gambetta,, M. C., & Furlong,, E. E. M. (2018). The insulator protein CTCF is required for correct Hox gene expression, but not for embryonic development in Drosophila. Genetics, 210(1), 129–136. https://doi.org/10.1534/genetics.118.301350
Gasperini,, M., Findlay,, G. M., McKenna,, A., Milbank,, J. H., Lee,, C., Zhang,, M. D., … Shendure,, J. (2017). CRISPR/Cas9‐mediated scanning for regulatory elements required for HPRT1 expression via thousands of large programmed genomic deletions. American Journal of Human Genetics, 101(2), 192–205. https://doi.org/10.1016/j.ajhg.2017.06.010
Gasperini,, M., Hill,, A. J., McFaline‐Figueroa,, J. L., Martin,, B., Kim,, S., Zhang,, M. D., … Shendure,, J. (2019). A genome‐wide framework for mapping gene regulation via cellular genetic screens. Cell, 176(1–2), 377–390.e19. https://doi.org/10.1016/j.cell.2018.11.029
Gentleman,, R. C., Parker,, M. H., Sanchez,, G. J., Yao,, Z., Davison,, J., MacQuarrie,, K. L., … Sarkar,, D. (2010). Genome‐wide MyoD binding in skeletal muscle cells: A potential for broad cellular reprogramming. Developmental Cell, 18(4), 662–674. https://doi.org/10.1016/j.devcel.2010.02.014
Ghavi‐Helm,, Y., Jankowski,, A., Meiers,, S., Viales,, R. R., Korbel,, J. O., & Furlong,, E. E. M. (2019). Highly rearranged chromosomes reveal uncoupling between genome topology and gene expression. Nature Genetics, 51, 1272–1282. https://doi.org/10.1038/s41588-019-0462-3
Ghirlando,, R., & Felsenfeld,, G. (2016). CTCF: Making the right connections. Genes and Development, 30(8), 881–891. https://doi.org/10.1101/gad.277863.116
Gilbert,, L. A., Horlbeck,, M. A., Adamson,, B., Villalta,, J. E., Chen,, Y., Whitehead,, E. H., … Weissman,, J. S. (2014). Genome‐scale CRISPR‐mediated control of gene repression and activation. Cell, 159(3), 647–661. https://doi.org/10.1016/j.cell.2014.09.029
Gilbert,, L. A., Larson,, M. H., Morsut,, L., Liu,, Z., Brar,, G. A., Torres,, S. E., … Qi,, L. S. (2013). CRISPR‐mediated modular RNA‐guided regulation of transcription in eukaryotes. Cell, 154(2), 442–451. https://doi.org/10.1016/j.cell.2013.06.044
Gisselbrecht,, S. S., Barrera,, L. A., Porsch,, M., Aboukhalil,, A., Estep,, P. W., Vedenko,, A., … Bulyk,, M. L. (2013). Highly parallel assays of tissue‐specific enhancers in whole Drosophila embryos. Nature Methods, 10(8), 774–780. https://doi.org/10.1038/nmeth.2558
Gomes,, A. L. C., Abeel,, T., Peterson,, M., Azizi,, E., Lyubetskaya,, A., Carvalho,, L., & Galagan,, J. (2014). Decoding ChIP‐seq with a double‐binding signal refines binding peaks to single‐nucleotides and predicts cooperative interaction. Genome Research, 24, 1686–1697. https://doi.org/10.1101/gr.161711.113
Goryshin,, I. Y., & Reznikoff,, W. S. (1998). Tn5 in vitro transposition. Journal of Biological Chemistry, 273(13), 7367–7374. https://doi.org/10.1074/jbc.273.13.7367
Gray,, S., & Levine,, M. (1996). Transcriptional repression in development. Current Opinion in Cell Biology, 8(3), 358–364. https://doi.org/10.1016/S0955-0674(96)80010-X
Groner,, A. C., Meylan,, S., Ciuffi,, A., Zangger,, N., Ambrosini,, G., Dénervaud,, N., … Trono,, D. (2010). KRAB‐zinc finger proteins and KAP1 can mediate long‐range transcriptional repression through heterochromatin spreading. PLoS Genetics, 6(3), e1000869. https://doi.org/10.1371/journal.pgen.1000869
Grosveld,, F., van Assendelft,, G. B., Greaves,, D. R., & Kollias,, G. (1987). Position‐independent, high‐level expression of the human β‐globin gene in transgenic mice. Cell, 51(6), 975–985. https://doi.org/10.1016/0092-8674(87)90584-8
Grunwald,, H. A., Gantz,, V. M., Poplawski,, G., Xu,, X. S., Bier,, E., & Cooper,, K. L. (2019). Super‐Mendelian inheritance mediated by CRISPR–Cas9 in the female mouse germline. Nature, 566(7742), 105–109. https://doi.org/10.1038/s41586-019-0875-2
Hagman,, J., Mansson,, R., Dutkowski,, J., Jhunjhunwala,, S., Benner,, C., Murre,, C., … Lin,, Y. C. (2010). A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate. Nature Immunology, 11(7), 635–643. https://doi.org/10.1038/ni.1891
Hainer,, S. J., Bošković,, A., McCannell,, K. N., Rando,, O. J., & Fazzio,, T. G. (2019). Profiling of pluripotency factors in single cells and early embryos. Cell, 177(5), 1319–1329. https://doi.org/10.1016/j.cell.2019.03.014
Halfon,, M. S., Carmena,, A., Gisselbrecht,, S., Sackerson,, C. M., Jiménez,, F., Baylies,, M. K., & Michelson,, A. M. (2000). Ras pathway specificity is determined by the integration of multiple signal‐activated and tissue‐restricted transcription factors. Cell, 103(1), 63–74. https://doi.org/10.1016/S0092-8674(00)00105-7
Hammar,, P., Leroy,, P., Mahmutovic,, A., Marklund,, E. G., Berg,, O. G., & Elf,, J. (2012). The lac repressor displays facilitated diffusion in living cells. Science, 336(6088), 1595–1598. https://doi.org/10.1126/science.1221648
Hay,, D., Hughes,, J. R., Babbs,, C., Davies,, J. O. J., Graham,, B. J., Hanssen,, L. L. P., … Higgs,, D. R. (2016). Genetic dissection of the α‐globin super‐enhancer in vivo. Nature Genetics, 48(8), 895–903. https://doi.org/10.1038/ng.3605
Heintzman,, N. D., Hon,, G. C., Hawkins,, R. D., Kheradpour,, P., Stark,, A., Harp,, L. F., … Ren,, B. (2009). Histone modifications at human enhancers reflect global cell‐type‐specific gene expression. Nature, 459(7243), 108–112. https://doi.org/10.1038/nature07829
Heintzman,, N. D., Stuart,, R. K., Hon,, G., Fu,, Y., Ching,, C. W., Hawkins,, R. D., … Ren,, B. (2007). Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nature Genetics, 39(3), 311–318. https://doi.org/10.1038/ng1966
Herz,, H. M., Mohan,, M., Garruss,, A. S., Liang,, K., Takahashi,, Y. H., Mickey,, K., … Shilatifard,, A. (2012). Enhancer‐associated H3K4 monomethylation by trithorax‐related, the Drosophila homolog of mammalian MLL3/MLL4. Genes and Development, 26(23), 2604–2620. https://doi.org/10.1101/gad.201327.112
Hnisz,, D., Abraham,, B. J., Lee,, T. I., Lau,, A., Saint‐André,, V., Sigova,, A. A., … Young,, R. A. (2013). Super‐enhancers in the control of cell identity and disease. Cell, 155(4), 934. https://doi.org/10.1016/j.cell.2013.09.053
Hnisz,, D., Shrinivas,, K., Young,, R. A., Chakraborty,, A. K., & Sharp,, P. A. (2017). A phase separation model for transcriptional control. Cell, 169(1), 13–23. https://doi.org/10.1016/j.cell.2017.02.007
Horlbeck,, M. A., Witkowsky,, L. B., Guglielmi,, B., Replogle,, J. M., Gilbert,, L. A., Villalta,, J. E., … Weissman,, J. S. (2016). Nucleosomes impede cas9 access to DNA in vivo and in vitro. eLife, 5, e12677. https://doi.org/10.7554/eLife.12677
Hosokawa,, H., Ungerbäck,, J., Wang,, X., Matsumoto,, M., Nakayama,, K. I., Cohen,, S. M., … Rothenberg,, E. V. (2018). Transcription factor PU.1 represses and activates gene expression in early T cells by redirecting partner transcription factor binding. Immunity, 48(6), 1119–1134. https://doi.org/10.1016/j.immuni.2018.04.024
Humbert,, R., Thurman,, R. E., Giste,, E., Lee,, B.‐K., Ebersol,, A. K., Furey,, T. S., … Dekker,, J. (2012). The accessible chromatin landscape of the human genome. Nature, 489(7414), 75–82. https://doi.org/10.1038/nature11232
Ing‐Simmons,, E., Seitan,, V. C., Faure,, A. J., Flicek,, P., Carroll,, T., Dekker,, J., … Merkenschlager,, M. (2015). Spatial enhancer clustering and regulation of enhancer‐proximal genes by cohesin. Genome Research, 25, 504–513. https://doi.org/10.1101/gr.184986.114
Jaitin,, D. A., Weiner,, A., Yofe,, I., Lara‐Astiaso,, D., Keren‐Shaul,, H., David,, E., … Amit,, I. (2016). Dissecting immune circuits by linking CRISPR‐pooled screens with single‐cell RNA‐Seq. Cell, 167(7), 1883–1896. https://doi.org/10.1016/j.cell.2016.11.039
Ji,, Z., Zhou,, W., & Ji,, H. (2017). Single‐cell regulome data analysis by SCRAT. Bioinformatics, 33(18), 2930–2932. https://doi.org/10.1093/bioinformatics/btx315
Jin,, C., Zang,, C., Wei,, G., Cui,, K., Peng,, W., Zhao,, K., & Felsenfeld,, G. (2009). H3.3/H2A.Z double variant‐containing nucleosomes mark “nucleosome‐free regions” of active promoters and other regulatory regions. Nature Genetics, 41(8), 941–945. https://doi.org/10.1038/ng.409
Jin,, W., Tang,, Q., Wan,, M., Cui,, K., Zhang,, Y., Ren,, G., … Zhao,, K. (2015). Genome‐wide detection of DNase I hypersensitive sites in single cells and FFPE tissue samples. Nature, 528, 142–146. https://doi.org/10.1038/nature15740
Jinek,, M., Chylinski,, K., Fonfara,, I., Hauer,, M., Doudna,, J. A., & Charpentier,, E. (2012). A programmable dual‐RNA‐guided DNA endonuclease in adaptive bacterial immunity. Science, 337(6096), 816–821. https://doi.org/10.1126/science.1225829
Jodkowska,, K., Pancaldi,, V., Almeida,, R., Rigau,, M., Pisano,, D., Valencia,, A., … Genomics,, S. (2019). Three‐dimensional connectivity and chromatin environment mediate the activation efficiency of mammalian DNA replication origins. BioRxiv.
Johnson,, D. S., Mortazavi,, A., Myers,, R. M., & Wold,, B. (2007). Genome‐wide mapping of in vivo protein–DNA interactions. Science, 316(5830), 1497–1502. https://doi.org/10.1126/science.1141319
Jung,, Y. L., Luquette,, L. J., Ho,, J. W. K., Ferrari,, F., Tolstorukov,, M., Minoda,, A., … Park,, P. J. (2014). Impact of sequencing depth in ChIP‐seq experiments. Nucleic Acids Research, 42(9), e74. https://doi.org/10.1093/nar/gku178
Kagey,, M. H., Newman,, J. J., Bilodeau,, S., Zhan,, Y., Orlando,, D. A., Van Berkum,, N. L., … Young,, R. A. (2010). Mediator and cohesin connect gene expression and chromatin architecture. Nature, 467(7314), 430–435. https://doi.org/10.1038/nature09380
Karaiskos,, N., Wahle,, P., Alles,, J., Boltengagen,, A., Ayoub,, S., Kipar,, C., … Zinzen,, R. P. (2017). The Drosophila embryo at single‐cell transcriptome resolution. Science, 358(6360), 194–199. https://doi.org/10.1126/science.aan3235
Kaya‐okur,, H. S., Wu,, S. J., Codomo,, C. A., Pledger,, E. S., Bryson,, T. D., Henikoff,, J. G., … Henikoff,, S. (2019). CUT%26Tag for efficient epigenomic profiling of small samples and single cells. Nature Communications, 10(1930), 1–10. https://doi.org/10.1038/s41467-019-09982-5
Kharchenko,, P. V., Alekseyenko,, A. A., Schwartz,, Y. B., Minoda,, A., Riddle,, N. C., Ernst,, J., … Park,, P. J. (2011). Comprehensive analysis of the chromatin landscape in Drosophila melanogaster. Nature, 471(7339), 480–485. https://doi.org/10.1038/nature09725
Kheradpour,, P., Ernst,, J., Melnikov,, A., Rogov,, P., Wang,, L., Zhang,, X., … Kellis,, M. (2013). Systematic dissection of regulatory motifs in 2000 predicted human enhancers using a massively parallel reporter assay. Genome Research, 23, 800–811. https://doi.org/10.1101/gr.144899.112
Kiselev,, V. Y., Andrews,, T. S., & Hemberg,, M. (2019). Challenges in unsupervised clustering of single‐cell RNA‐seq data. Nature Reviews Genetics, 20(5), 273–282. https://doi.org/10.1038/s41576-018-0088-9
Kolodziejczyk,, A. A., Kim,, J. K., Svensson,, V., Marioni,, J. C., & Teichmann,, S. A. (2015). The technology and biology of single‐cell RNA sequencing. Molecular Cell, 58(4), 610–620. https://doi.org/10.1016/j.molcel.2015.04.005
Korkmaz,, G., Lopes,, R., Ugalde,, A. P., Nevedomskaya,, E., Han,, R., Myacheva,, K., … Agami,, R. (2016). Functional genetic screens for enhancer elements in the human genome using CRISPR‐Cas9. Nature Biotechnology, 34(2), 192–198. https://doi.org/10.1038/nbt.3450
Kramer,, N. J., Haney,, M. S., Morgens,, D. W., Jovičić,, A., Couthouis,, J., Li,, A., … Gitler,, A. D. (2018). CRISPR‐Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide‐repeat‐protein toxicity. Nature Genetics, 50(4), 603–612. https://doi.org/10.1038/s41588-018-0070-7
Kubo,, N., Ishii,, H., Gorkin,, D., Meitinger,, F., Xiong,, X., Fang,, R., … Ren,, B. (2017). Preservation of chromatin organization after acute loss of CTCF in mouse embryonic stem cells. BioRxiv. https://doi.org/10.1101/118737
Kurum,, E., Benayoun,, B. A., Malhotra,, A., George,, J., & Ucar,, D. (2016). Computational inference of a genomic pluripotency signature in human and mouse stem cells. Biology Direct, 11, 47. https://doi.org/10.1186/s13062-016-0148-z
Kvon,, E. Z., Stampfel,, G., Omar Yáññez‐Cuna,, J., Dickson,, B. J., & Stark,, A. (2012). HOT regions function as patterned developmental enhancers and have a distinct cis‐regulatory signature. Genes and Development, 26(9), 908–913. https://doi.org/10.1101/gad.188052.112
Kwasnieski,, J. C., Fiore,, C., Chaudhari,, H. G., & Cohen,, B. A. (2014). High‐throughput functional testing of ENCODE segmentation predictions. Genome Research, 24, 1595–1602. https://doi.org/10.1101/gr.173518.114
Lai,, B., Gao,, W., Cui,, K., Xie,, W., Tang,, Q., Jin,, W., … Zhao,, K. (2018). Principles of nucleosome organization revealed by single‐cell micrococcal nuclease sequencing. Nature, 562, 281–285. https://doi.org/10.1038/s41586-018-0567-3
Landt,, S. G., Marinov,, G. K., Kundaje,, A., Kheradpour,, P., Pauli,, F., Batzoglou,, S., … Snyder,, M. (2012). ChIP‐seq guidelines and practices of the ENCODE and modENCODE consortia. Genome Research, 22(9), 1813–1831. https://doi.org/10.1101/gr.136184.111
Lareau,, C. A., Ulirsch,, J. C., Bao,, E. L., Ludwig,, L. S., Finucane,, H. K., Aryee,, M. J., … Sankaran,, V. G. (2018). Interrogation of human hematopoiesis at single‐cell and single‐variant resolution. BioRxiv. https://doi.org/10.1101/255224
LeProust,, E. M., Peck,, B. J., Spirin,, K., McCuen,, H. B., Moore,, B., Namsaraev,, E., & Caruthers,, M. H. (2010). Synthesis of high‐quality libraries of long (150mer) oligonucleotides by a novel depurination controlled process. Nucleic Acids Research, 38(8), 2522–2540. https://doi.org/10.1093/nar/gkq163
Lettice,, L. A., Heaney,, S. J. H., Purdie,, L. A., Li,, L., de Beer,, P., Oostra,, B. A., … de Graaff,, E. (2003). A long‐range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Human Molecular Genetics, 12(14), 1725–1735. https://doi.org/10.1093/hmg/ddg180
Levine,, M. (2010). Transcriptional enhancers in animal development and evolution. Current Biology, 20(17), R754–R763. https://doi.org/10.1016/j.cub.2010.06.070
Li,, G., Ruan,, X., Auerbach,, R. K., Sandhu,, K. S., Zheng,, M., Wang,, P., … Ruan,, Y. (2012). Extensive promoter‐centered chromatin interactions provide a topological basis for transcription regulation. Cell, 148(1), 84–98. https://doi.org/10.1016/j.cell.2011.12.014
Li,, Q., Peterson,, K. R., Fang,, X., & Stamatoyannopoulos,, G. (2002). Locus control regions. Blood, 100(9), 3077–3086. https://doi.org/10.1182/blood-2002-04-1104.BLOOD
Li,, X. Y., MacArthur,, S., Bourgon,, R., Nix,, D., Pollard,, D. A., Iyer,, V. N., … Biggin,, M. D. (2008). Transcription factors bind thousands of active and inactive regions in the Drosophila blastoderm. PLoS Biology, 6(7), e190. https://doi.org/10.1371/journal.pbio.0060027
Lieberman‐Aiden,, E., Van Berkum,, N. L., Williams,, L., Imakaev,, M., Ragoczy,, T., Telling,, A., … Dekker,, J. (2009). Comprehensive mapping of long‐range interactions reveals folding principles of the human genome. Science, 326(5950), 289–293. https://doi.org/10.1126/science.1181369
Lovén,, J., Hoke,, H. A., Lin,, C. Y., Lau,, A., Orlando,, D. A., Vakoc,, C. R., … Young,, R. A. (2013). Selective inhibition of tumor oncogenes by disruption of super‐enhancers. Cell, 153(2), 320–334. https://doi.org/10.1016/j.cell.2013.03.036
Lubeck,, E., & Cai,, L. (2012). Single‐cell systems biology by super‐resolution imaging and combinatorial labeling. Nature Methods, 9(7), 743–748. https://doi.org/10.1038/nmeth.2069
Lubeck,, E., Coskun,, A. F., Zhiyentayev,, T., Ahmad,, M., & Cai,, L. (2014). Single‐cell in situ RNA profiling by sequential hybridization. Nature Methods, 11(4), 360–361. https://doi.org/10.1038/nmeth.2892
Lupiáñez,, D. G., Kraft,, K., Heinrich,, V., Krawitz,, P., Brancati,, F., Klopocki,, E., … Mundlos,, S. (2015). Disruptions of topological chromatin domains cause pathogenic rewiring of gene‐enhancer interactions. Cell, 161(5), 1012–1025. https://doi.org/10.1016/j.cell.2015.04.004
MacArthur,, S., Pfeiffer,, B. D., Eisen,, M. B., Stamatoyannopoulos,, J. A., Bickel,, P. J., Li,, J. J., … Celniker,, S. E. (2012). DNA regions bound at low occupancy by transcription factors do not drive patterned reporter gene expression in Drosophila. Proceedings of the National Academy of Sciences, 109(52), 21330–21335. https://doi.org/10.1073/pnas.1209589110
Macosko,, E. Z., Basu,, A., Satija,, R., Nemesh,, J., Shekhar,, K., Goldman,, M., … McCarroll,, S. A. (2015). Highly parallel genome‐wide expression profiling of individual cells using nanoliter droplets. Cell, 161(5), 1202–1214. https://doi.org/10.1016/j.cell.2015.05.002
Maeder,, M. L., Linder,, S. J., Cascio,, V. M., Fu,, Y., Ho,, Q. H., & Joung,, J. K. (2013). CRISPR RNA‐guided activation of endogenous human genes. Nature Methods, 10(10), 977–979. https://doi.org/10.1038/nmeth.2598
Mahony,, S., & Pugh,, B. F. (2015). Protein‐DNA binding in high‐resolution. Critical Reviews in Biochemistry and Molecular Biology, 50(4), 269–283. https://doi.org/10.3109/10409238.2015.1051505
Mali,, P., Yang,, L., Esvelt,, K. M., Aach,, J., Guell,, M., DiCarlo,, J. E., … Church,, G. M. (2013). RNA‐guided human genome engineering via Cas9. Science, 339(6121), 823–826. https://doi.org/10.1126/science.1232033
May,, D., Blow,, M. J., Kaplan,, T., McCulley,, D. J., Jensen,, B. C., Akiyama,, J. A., … Visel,, A. (2012). Large‐scale discovery of enhancers from human heart tissue. Nature Genetics, 44(1), 89–93. https://doi.org/10.1038/ng.1006
McSwiggen,, D. T., Hansen,, A. S., Teves,, S. S., Marie‐Nelly,, H., Hao,, Y., Heckert,, A. B., … Darzacq,, X. (2019). Evidence for DNA‐mediated nuclear compartmentalization distinct from phase separation. eLife, 8, 1–31. https://doi.org/10.7554/eLife.47098
Meador,, J. P., Lech,, J. J., Rice,, S. D., Hose,, J. E., Short,, J. W., Rice,, S. D., … White,, E. (2014). Massively parallel single‐cell RNA‐Seq for marker‐free decomposition of tissues into cell types. Science, 343, 776–779.
Medina,, C., Valouev,, A., Sidow,, A., Batzoglou,, S., Sundquist,, A., Myers,, R. M., … Johnson,, D. S. (2008). Genome‐wide analysis of transcription factor binding sites based on ChIP‐Seq data. Nature Methods, 5(9), 829–834. https://doi.org/10.1038/nmeth.1246
Meireles‐Filho,, A. C., & Stark,, A. (2009). Comparative genomics of gene regulation‐conservation and divergence of cis‐regulatory information. Current Opinion in Genetics and Development, 19(6), 565–570. https://doi.org/10.1016/j.gde.2009.10.006
Melnikov,, A., Murugan,, A., Zhang,, X., Tesileanu,, T., Wang,, L., Rogov,, P., … Mikkelsen,, T. S. (2012). Systematic dissection and optimization of inducible enhancers in human cells using a massively parallel reporter assay. Nature Biotechnology, 30(3), 271–277. https://doi.org/10.1038/nbt.2137
Merkenschlager,, M., & Nora,, E. P. (2016). CTCF and Cohesin in genome folding and transcriptional gene regulation. Annual Review of Genomics and Human Genetics, 17(1), 17–43. https://doi.org/10.1146/annurev-genom-083115-022339
Mir,, M., Bickmore,, W., Furlong,, E. E. M., & Narlikar,, G. (2019). Chromatin topology, condensates and gene regulation: Shifting paradigms or just a phase? Development, 146, dev182766. https://doi.org/10.1242/dev.182766
Mir,, M., Stadler,, M. R., Ortiz,, S. A., Hannon,, C. E., Harrison,, M. M., Darzacq,, X., & Eisen,, M. B. (2018). Dynamic multifactor hubs interact transiently with sites of active transcription in Drosophila embryos. eLife, 7, 1–27. https://doi.org/10.7554/eLife.40497
Moffitt,, J. R., Bambah‐Mukku,, D., Eichhorn,, S. W., Vaughn,, E., Shekhar,, K., Perez,, J. D., … Zhuang,, X. (2018). Molecular, spatial, and functional single‐cell profiling of the hypothalamic preoptic region. Science, 362(6416), eaau5324. https://doi.org/10.1126/science.aau5324
Mogno,, I., Kwasnieski,, J. C., Cohen,, B. A., Myers,, C. A., & Corbo,, J. C. (2012). Complex effects of nucleotide variants in a mammalian cis‐regulatory element. Proceedings of the National Academy of Sciences, 109(47), 19498–19503. https://doi.org/10.1073/pnas.1210678109
Moreau,, P., Hen,, R., Wasylyk,, B., Everett,, R., Gaub,, M. P., & Chambon,, P. (1981). The SV40 72 base repair repeat has a striking effect on gene expression both in SV40 and other chimeric recombinants. Nucleic Acids Research, 9(22), 6047–6068. https://doi.org/10.1093/nar/9.22.6047
Munsky,, B., Neuert,, G., & Van Oudenaarden,, A. (2012). Using gene expression noise to understand gene regulation. Science, 336, 183–187. https://doi.org/10.1126/science.1216379
Nagano,, T., Lubling,, Y., Stevens,, T. J., Schoenfelder,, S., Yaffe,, E., Dean,, W., … Fraser,, P. (2013). Single‐cell Hi‐C reveals cell‐to‐cell variability in chromosome structure. Nature, 502(7469), 59–64. https://doi.org/10.1038/nature12593
Nakamura,, M., Srinivasan,, P., Chavez,, M., Carter,, M. A., Dominguez,, A. A., La Russa,, M., … Qi,, L. S. (2019). Anti‐CRISPR‐mediated control of gene editing and synthetic circuits in eukaryotic cells. Nature Communications, 10(1), 194. https://doi.org/10.1038/s41467-018-08158-x
Nakayama,, T., Fish,, M. B., Fisher,, M., Oomen‐Hajagos,, J., Thomsen,, G. H., & Grainger,, R. M. (2013). Simple and efficient CRISPR/Cas9‐mediated targeted mutagenesis in Xenopus tropicalis. Genesis, 51(12), 835–843. https://doi.org/10.1002/dvg.22720
Nettling,, M., Treutler,, H., Cerquides,, J., & Grosse,, I. (2016). Detecting and correcting the binding‐affinity bias in ChIP‐seq data using inter‐species information. BMC Genomics, 17, 347. https://doi.org/10.1186/s12864-016-2682-6
Nora,, E. P., Lajoie,, B. R., Schulz,, E. G., Giorgetti,, L., Okamoto,, I., Servant,, N., … Heard,, E. (2012). Spatial partitioning of the regulatory landscape of the X‐inactivation centre. Nature, 485(7398), 381–385. https://doi.org/10.1038/nature11049
Ostuni,, R., Piccolo,, V., Barozzi,, I., Polletti,, S., Termanini,, A., Bonifacio,, S., … Natoli,, G. (2013). Latent enhancers activated by stimulation in differentiated cells. Cell, 152(1), 157–171. https://doi.org/10.1016/j.cell.2012.12.018
Parker,, S. C. J., Stitzel,, M. L., Taylor,, D. L., Orozco,, J. M., Erdos,, M. R., Akiyama,, J. A., … Collins,, F. S. (2013). Chromatin stretch enhancer states drive cell‐specific gene regulation and harbor human disease risk variants. Proceedings of the National Academy of Sciences of the United States of America, 110(44), 17921–17926. https://doi.org/10.1073/pnas.1317023110
Patwardhan,, R. P., Hiatt,, J. B., Witten,, D. M., Kim,, M. J., Smith,, R. P., May,, D., … Shendure,, J. (2012). Massively parallel functional dissection of mammalian enhancers in vivo. Nature Biotechnology, 30(3), 265–270. https://doi.org/10.1038/nbt.2136
Perez‐Pinera,, P., Kocak,, D. D., Vockley,, C. M., Adler,, A. F., Kabadi,, A. M., Polstein,, L. R., … Gersbach,, C. A. (2013). RNA‐guided gene activation by CRISPR‐Cas9‐based transcription factors. Nature Methods, 10(10), 973–976. https://doi.org/10.1038/nmeth.2600
Peters,, A. H., Mermoud,, J. E., O`Carroll,, D., Pagani,, M., Schweizer,, D., Brockdorff,, N., & Jenuwein,, T. (2002). Histone H3 lysine 9 methylation is an epigenetic imprint of facultative heterochromatin. Nature Genetics, 30(1), 77–80. https://doi.org/10.1038/ng789
Phillips‐Cremins,, J. E., Sauria,, M. E. G., Sanyal,, A., Gerasimova,, T. I., Lajoie,, B. R., Bell,, J. S. K., … Corces,, V. G. (2013). Architectural protein subclasses shape 3D organization of genomes during lineage commitment. Cell, 153(6), 1281–1295. https://doi.org/10.1016/j.cell.2013.04.053
Pijuan‐Sala,, B., Griffiths,, J. A., Guibentif,, C., Hiscock,, T. W., Jawaid,, W., Calero‐Nieto,, F. J., … Göttgens,, B. (2019). A single‐cell molecular map of mouse gastrulation and early organogenesis. Nature, 566(7745), 490–495. https://doi.org/10.1038/s41586-019-0933-9
Pilon,, A. M., Ajay,, S. S., Kumar,, S. A., Steiner,, L. A., Cherukuri,, P. F., Wincovitch,, S., … Bodine,, D. M. (2011). Genome‐wide ChIP‐Seq reveals a dramatic shift in the binding of the transcription factor erythroid Kruppel‐like factor during erythrocyte differentiation. Blood, 118(17), 139–149. https://doi.org/10.1182/blood-2011-05-355107
Plass,, M., Solana,, J., Alexander Wolf,, F., Ayoub,, S., Misios,, A., Glažar,, P., … Rajewsky,, N. (2018). Cell type atlas and lineage tree of a whole complex animal by single‐cell transcriptomics. Science, 360(6391), eaaq1723. https://doi.org/10.1126/science.aaq1723
Pollen,, A. A., Nowakowski,, T. J., Shuga,, J., Wang,, X., Leyrat,, A. A., Lui,, J. H., … West,, J. A. A. (2014). Low‐coverage single‐cell mRNA sequencing reveals cellular heterogeneity and activated signaling pathways in developing cerebral cortex. Nature Biotechnology, 32(10), 1053–1058. https://doi.org/10.1038/nbt.2967
Pope,, B. D., Ryba,, T., Dileep,, V., Yue,, F., Wu,, W., Denas,, O., … Gilbert,, D. M. (2014). Topologically associating domains are stable units of replication‐timing regulation. Nature, 515(7527), 402–405. https://doi.org/10.1038/nature13986
Pott,, S., & Lieb,, J. D. (2015). What are super‐enhancers? Nature Genetics, 47(1), 8–12. https://doi.org/10.1038/ng.3167
Racioppi,, C., Wiechecki,, K. A., & Christiaen,, L. (2019). Combinatorial chromatin dynamics foster accurate cardiopharyngeal fate choices. BioRxiv.
Rada‐Iglesias,, A., Bajpai,, R., Swigut,, T., Brugmann,, S. A., Flynn,, R. A., & Wysocka,, J. (2011). A unique chromatin signature uncovers early developmental enhancers in humans. Nature, 470(7333), 279–283. https://doi.org/10.1038/nature09692
Rajagopal,, N., Srinivasan,, S., Kooshesh,, K., Guo,, Y., Edwards,, M. D., Banerjee,, B., … Sherwood,, R. I. (2016). High‐throughput mapping of regulatory DNA. Nature Biotechnology, 34(2), 167–174. https://doi.org/10.1038/nbt.3468
Ramos,, A. I., & Barolo,, S. (2013). Low‐affinity transcription factor binding sites shape morphogen responses and enhancer evolution. Philosophical Transactions of the Royal Society, B: Biological Sciences, 368, 20130018. https://doi.org/10.1098/rstb.2013.0018
Rao,, S. S. P., Huntley,, M. H., Durand,, N. C., Stamenova,, E. K., Bochkov,, I. D., Robinson,, J. T., … Aiden,, E. L. (2014). A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell, 159(7), 1665–1680. https://doi.org/10.1016/j.cell.2014.11.021
Raviram,, R., Rocha,, P. P., Bonneau,, R., & Skok,, J. A. (2014). Interpreting 4C‐Seq data: How far can we go? Epigenomics, 6(5), 455–457. https://doi.org/10.2217/epi.14.47
Reynolds,, N., Salmon‐Divon,, M., Dvinge,, H., Hynes‐Allen,, A., Balasooriya,, G., Leaford,, D., … Hendrich,, B. (2012). NuRD‐mediated deacetylation of H3K27 facilitates recruitment of Polycomb repressive complex 2 to direct gene repression. The EMBO Journal, 31(3), 593–605. https://doi.org/10.1038/emboj.2011.431
Rhee,, H. S., & Pugh,, B. F. (2011). Comprehensive genome‐wide protein‐DNA interactions detected at single‐nucleotide resolution. Cell, 147(6), 1408–1419. https://doi.org/10.1016/j.cell.2011.11.013
Robertson,, G., Bernier,, B., Zhao,, Y., Varhol,, R., Snyder,, M., Euskirchen,, G., … Bilenky,, M. (2007). Genome‐wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing. Nature Methods, 4(8), 651–657. https://doi.org/10.1038/nmeth1068
Roh,, T. Y., Cuddapah,, S., & Zhao,, K. (2005). Active chromatin domains are defined by acetylation islands revealed by genome‐wide mapping. Genes and Development, 19(5), 542–552. https://doi.org/10.1101/gad.1272505
Ron,, G., Globerson,, Y., Moran,, D., & Kaplan,, T. (2017). Promoter‐enhancer interactions identified from Hi‐C data using probabilistic models and hierarchical topological domains. Nature Communications, 8(1), 2237. https://doi.org/10.1038/s41467-017-02386-3
Rotem,, A., Ram,, O., Shoresh,, N., Sperling,, R. A., Goren,, A., Weitz,, D. A., & Bernstein,, B. E. (2015). Single‐cell ChIP‐seq reveals cell subpopulations defined by chromatin state. Nature Biotechnology, 33(11), 1165–1172. https://doi.org/10.1038/nbt.3383
Rothbacher,, U., Bertrand,, V., Lamy,, C., & Lemaire,, P. (2007). A combinatorial code of maternal GATA, Ets and ‐catenin‐TCF transcription factors specifies and patterns the early ascidian ectoderm. Development, 134(22), 4023–4032. https://doi.org/10.1242/dev.010850
Rowan,, S., Siggers,, T., Lachke,, S. A., Yue,, Y., Bulyk,, M. L., & Maas,, R. L. (2010). Precise temporal control of the eye regulatory gene Pax6 via enhancer‐binding site affinity. Genes and Development, 24(10), 980–985. https://doi.org/10.1101/gad.1890410
Rye,, M. B., Sætrom,, P., & Drabløs,, F. (2011). A manually curated ChIP‐seq benchmark demonstrates room for improvement in current peak‐finder programs. Nucleic Acids Research, 39, e25. https://doi.org/10.1093/nar/gkq1187
Sabari,, B. R., Dall`Agnese,, A., Boija,, A., Klein,, I. A., Coffey,, E. L., Shrinivas,, K., … Young,, R. A. (2018). Coactivator condensation at super‐enhancers links phase separation and gene control. Science, 361(6400), eaar3958. https://doi.org/10.1126/science.aap9195
Sandelin,, A. (2004). JASPAR: An open‐access database for eukaryotic transcription factor binding profiles. Nucleic Acids Research, 32, D91–D94. https://doi.org/10.1093/nar/gkh012
Sandmann,, T., Girardot,, C., Brehme,, M., Tongprasit,, W., Stolc,, V., & Furlong,, E. E. M. (2007). A core transcriptional network for early mesoderm development in Drosophila melanogaster. Genes and Development, 21(4), 436–449. https://doi.org/10.1101/gad.1509007
Sanjana,, N. E., Wright,, J., Zheng,, K., Shalem,, O., Fontanillas,, P., Joung,, J., … Zhang,, F. (2016). High‐resolution interrogation of functional elements in the noncoding genome. Science, 353(6307), 1545–1549. https://doi.org/10.1126/science.aaf7613
Sarro,, R., Kocher,, A. A., Emera,, D., Uebbing,, S., Dutrow,, E. V., Weatherbee,, S. D., … Noonan,, J. P. (2018). Disrupting the three‐dimensional regulatory topology of the Pitx1 locus results in overtly normal development. Development, 145(7), dev158550. https://doi.org/10.1242/dev.158550
Sasai,, Y., Lu,, B., Steinbeisser,, H., Geissert,, D., Gont,, L. K., & De Robertis,, E. M. (1994). Xenopus chordin: A novel dorsalizing factor activated by organizer‐specific homeobox genes. Cell, 79(5), 779–790. https://doi.org/10.1016/0092-8674(94)90068-X
Schep,, A. N., Wu,, B., Buenrostro,, J. D., & Greenleaf,, W. J. (2017). ChromVAR: Inferring transcription‐factor‐associated accessibility from single‐cell epigenomic data. Nature Methods, 14(10), 975–978. https://doi.org/10.1038/nmeth.4401
Schmidt,, D., Schwalie,, P. C., Ross‐Innes,, C. S., Hurtado,, A., Brown,, G. D., Carroll,, J. S., … Odom,, D. T. (2010). A CTCF‐independent role for cohesin in tissue‐specific transcription. Genome Research, 20(5), 578–588. https://doi.org/10.1101/gr.100479.109
Schmitt,, A. D., Hu,, M., Jung,, I., Xu,, Z., Qiu,, Y., Tan,, C. L., … Ren,, B. (2016). A compendium of chromatin contact maps reveals spatially active regions in the human genome. Cell Reports, 17(8), 2042–2059. https://doi.org/10.1016/j.celrep.2016.10.061
Schöne,, S., Meijsing,, S. H., Thomas‐Chollier,, M., Bothe,, M., Vingron,, M., Borschiwer,, M., … Einfeldt,, E. (2018). Synthetic STARR‐seq reveals how DNA shape and sequence modulate transcriptional output and noise. PLoS Genetics, 14(11), e1007793. https://doi.org/10.1371/journal.pgen.1007793
Schones,, D. E., Cui,, K., Cuddapah,, S., Roh,, T. Y., Barski,, A., Wang,, Z., … Zhao,, K. (2008). Dynamic regulation of nucleosome positioning in the human genome. Cell, 132(5), 887–898. https://doi.org/10.1016/j.cell.2008.02.022
Schulte‐Merker,, S., Lee,, K. J., McMahon,, A. P., & Hammerschmidt,, M. (1997). The zebrafish organizer requires chordino. Nature, 387(6636), 862–863. https://doi.org/10.1038/43092
Schultz,, D. C., Ayyanathan,, K., Negorev,, D., Maul,, G. G., & Rauscher,, F. J. (2002). SETDB1: A novel KAP‐1‐associated histone H3, lysine 9‐specific methyltransferase that contributes to HP1‐mediated silencing of euchromatic genes by KRAB zinc‐finger proteins. Genes and Development, 16(8), 919–932. https://doi.org/10.1101/gad.973302
Schwarzer,, W., Abdennur,, N., Goloborodko,, A., Pekowska,, A., Fudenberg,, G., Loe‐Mie,, Y., … Spitz,, F. (2017). Two independent modes of chromatin organization revealed by cohesin removal. Nature, 551(7678), 51–56. https://doi.org/10.1038/nature24281
Seipel,, K., Georgiev,, O., & Schaffner,, W. (1992). Different activation domains stimulate transcription from remote (‘enhancer’) and proximal (‘promoter’) positions. The EMBO Journal, 11(13), 4961–4968.
Shalek,, A. K., Satija,, R., Adiconis,, X., Gertner,, R. S., Gaublomme,, J. T., Raychowdhury,, R., … Regev,, A. (2013). Single‐cell transcriptomics reveals bimodality in expression and splicing in immune cells. Nature, 498(7453), 236–240. https://doi.org/10.1038/nature12172
Shan,, Q., Wang,, Y., Li,, J., Zhang,, Y., Chen,, K., Liang,, Z., … Gao,, C. (2013). Targeted genome modification of crop plants using a CRISPR‐Cas system. Nature Biotechnology, 31(8), 686–688. https://doi.org/10.1038/nbt.2623
Shen,, Y., Diao,, Y., Li,, B., Ren,, B., Fang,, R., Lin,, K. C., … Huang,, H. (2017). A tiling‐deletion‐based genetic screen for cis‐regulatory element identification in mammalian cells. Nature Methods, 14(6), 629–635. https://doi.org/10.1038/nmeth.4264
Shen,, Y., Yue,, F., Mc Cleary,, D. F., Ye,, Z., Edsall,, L., Kuan,, S., … Lobanenkov,, V. V. (2012). A map of the cis‐regulatory sequences in the mouse genome. Nature, 488(7409), 116–120. https://doi.org/10.1038/nature11243
Shilatifard,, A. (2012). The COMPASS family of histone H3K4 methylases: Mechanisms of regulation in development and disease pathogenesis. Annual Review of Biochemistry, 81, 65–95. https://doi.org/10.1146/annurev-biochem-051710-134100
Shin,, H. Y., Willi,, M., Yoo,, K. H., Zeng,, X., Wang,, C., Metser,, G., & Hennighausen,, L. (2016). Hierarchy within the mammary STAT5‐driven Wap super‐enhancer. Nature Genetics, 48(8), 904–911. https://doi.org/10.1038/ng.3606
Shlyueva,, D., Stampfel,, G., & Stark,, A. (2014). Transcriptional enhancers: From properties to genome‐wide predictions. Nature Reviews Genetics, 15(4), 272–286. https://doi.org/10.1038/nrg3682
Shrinivas,, K., Sabari,, B. R., Coffey,, E. L., Klein,, I. A., Boija,, A., Zamudio,, A. V., … Chakraborty,, A. K. (2019). Enhancer features that drive formation of transcriptional condensates. Molecular Cell, 75, 549–561. https://doi.org/10.1016/j.molcel.2019.07.009
Simeonov,, D. R., Ansel,, K. M., Gagnon,, J. D., Tobin,, V. R., Farh,, K. K., Schumann,, K., … Satpathy,, A. T. (2017). Discovery of stimulation‐responsive immune enhancers with CRISPR activation. Nature, 549(7670), 111–115. https://doi.org/10.1038/nature23875
Skene,, P. J., & Henikoff,, S. (2017). An efficient targeted nuclease strategy for high‐resolution mapping of DNA binding sites. eLife, 6, 1–35. https://doi.org/10.7554/eLife.21856
Soshnikova,, N., Montavon,, T., Leleu,, M., Galjart,, N., & Duboule,, D. (2010). Functional analysis of CTCF during mammalian limb development. Developmental Cell, 19(6), 819–830. https://doi.org/10.1016/j.devcel.2010.11.009
Sripathy,, S. P., Stevens,, J., & Schultz,, D. C. (2006). The KAP1 corepressor functions to coordinate the assembly of de novo HP1‐demarcated microenvironments of heterochromatin required for KRAB zinc finger protein‐mediated transcriptional repression. Molecular and Cellular Biology, 26(22), 8623–8638. https://doi.org/10.1128/mcb.00487-06
Ståhl,, P. L., Salmén,, F., Vickovic,, S., Lundmark,, A., Navarro,, J. F., Magnusson,, J., … Frisén,, J. (2016). Visualization and analysis of gene expression in tissue sections by spatial transcriptomics. Science, 363(6294), 78–82. https://doi.org/10.1126/science.aaf2403
Stolfi,, A., Gandhi,, S., Salek,, F., & Christiaen,, L. (2014). Tissue‐specific genome editing in ciona embryos by CRISPR/Cas9. Development, 141(21), 4115–4120. https://doi.org/10.1242/dev.114488
Symmons,, O., Pan,, L., Remeseiro,, S., Aktas,, T., Klein,, F., Huber,, W., & Spitz,, F. (2016). The Shh topological domain facilitates the action of remote enhancers by reducing the effects of genomic distances. Developmental Cell, 39(5), 529–543. https://doi.org/10.1016/j.devcel.2016.10.015
Symmons,, O., Uslu,, V. V., Tsujimura,, T., Ruf,, S., Nassari,, S., Schwarzer,, W., … Spitz,, F. (2014). Functional and topological characteristics of mammalian regulatory domains. Genome Research, 24(3), 390–400. https://doi.org/10.1101/gr.163519.113
Tang,, F., Barbacioru,, C., Bao,, S., Lee,, C., Nordman,, E., Wang,, X., … Surani,, M. A. (2010). Tracing the derivation of embryonic stem cells from the inner cell mass by single‐cell RNA‐seq analysis. Cell Stem Cell, 6(5), 468–478. https://doi.org/10.1016/j.stem.2010.03.015
Tang,, F., Barbacioru,, C., Wang,, Y., Nordman,, E., Lee,, C., Xu,, N., … Surani,, M. A. (2009). mRNA‐Seq whole‐transcriptome analysis of a single cell. Nature Methods, 6(5), 377–382. https://doi.org/10.1038/nmeth.1315
Tang,, Z., Luo,, O. J., Li,, X., Zheng,, M., Zhu,, J. J., Szalaj,, P., … Ruan,, Y. (2015). CTCF‐mediated human 3D genome architecture reveals chromatin topology for transcription. Cell, 163(7), 1611–1627. https://doi.org/10.1016/j.cell.2015.11.024
Tewhey,, R., Kotliar,, D., Park,, D. S., Liu,, B., Winnicki,, S., Reilly,, S. K., … Sabeti,, P. C. (2016). Direct identification of hundreds of expression‐modulating variants using a multiplexed reporter assay. Cell, 165(6), 1519–1529. https://doi.org/10.1016/j.cell.2016.04.027
Teytelman,, L., Thurtle,, D. M., Rine,, J., & van Oudenaarden,, A. (2013). Highly expressed loci are vulnerable to misleading ChIP localization of multiple unrelated proteins. Proceedings of the National Academy of Sciences, 110(46), 18602–18607. https://doi.org/10.1073/pnas.1316064110
Tolhuis,, B., Palstra,, R. J., Splinter,, E., Grosveld,, F., & De Laat,, W. (2002). Looping and interaction between hypersensitive sites in the active β‐globin locus. Molecular Cell, 10(6), 1453–1465. https://doi.org/10.1016/S1097-2765(02)00781-5
Trapnell,, C., Cacchiarelli,, D., Grimsby,, J., Pokharel,, P., Li,, S., Morse,, M., … Rinn,, J. L. (2014). The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nature Biotechnology, 32(4), 381–386. https://doi.org/10.1038/nbt.2859
Trapnell,, C., & Liu,, S. (2016). Single‐cell transcriptome sequencing: Recent advances and remaining challenges. F1000Research, 5, 182. https://doi.org/10.12688/f1000research.7223.1
Valouev,, A., Johnson,, S. M., Boyd,, S. D., Smith,, C. L., Fire,, A. Z., & Sidow,, A. (2011). Determinants of nucleosome organization in primary human cells. Nature, 474(7352), 516–520. https://doi.org/10.1038/nature10002
Van Steensel,, B., & Dekker,, J. (2010). Genomics tools for unraveling chromosome architecture. Nature Biotechnology, 28(10), 1089–1095. https://doi.org/10.1038/nbt.1680
Vastenhouw,, N. L., Zhang,, Y., Woods,, I. G., Imam,, F., Regev,, A., Liu,, X. S., … Schier,, A. F. (2010). Chromatin signature of embryonic pluripotency is established during genome activation. Nature, 464(7290), 922–926. https://doi.org/10.1038/nature08866
Visel,, A., Blow,, M. J., Li,, Z., Zhang,, T., Akiyama,, J. A., Holt,, A., … Pennacchio,, L. A. (2009). ChIP‐seq accurately predicts tissue‐specific activity of enhancers. Nature, 457(7231), 854–858. https://doi.org/10.1038/nature07730
Visel,, A., Taher,, L., Girgis,, H., May,, D., Golonzhka,, O., Hoch,, R. V., … Rubenstein,, J. L. R. (2013). A high‐resolution enhancer atlas of the developing telencephalon. Cell, 152(4), 895–908. https://doi.org/10.1016/j.cell.2012.12.041
Wagner,, D. E., Weinreb,, C., Collins,, Z. M., Briggs,, J. A., Megason,, S. G., & Klein,, A. M. (2018). Single‐cell mapping of gene expression landscapes and lineage in the zebrafish embryo. Science, 360(6392), 981–987. https://doi.org/10.1126/science.aar4362
Wamstad,, J. A., Alexander,, J. M., Truty,, R. M., Shrikumar,, A., Li,, F., Eilertson,, K. E., … Bruneau,, B. G. (2012). Dynamic and coordinated epigenetic regulation of developmental transitions in the cardiac lineage. Cell, 151(1), 206–220. https://doi.org/10.1016/j.cell.2012.07.035
Wang,, H., Yang,, H., Shivalila,, C. S., Dawlaty,, M. M., Cheng,, A. W., Zhang,, F., & Jaenisch,, R. (2013). One‐step generation of mice carrying mutations in multiple genes by CRISPR/cas‐mediated genome engineering. Cell, 153(4), 910–918. https://doi.org/10.1016/j.cell.2013.04.025
Whyte,, W. A., Orlando,, D. A., Hnisz,, D., Abraham,, B. J., Lin,, C. Y., Kagey,, M. H., … Young,, R. A. (2013). Master transcription factors and mediator establish super‐enhancers at key cell identity genes. Cell, 153(2), 307–319. https://doi.org/10.1016/j.cell.2013.03.035
Williamson,, I., Kane,, L., Devenney,, P. S., Anderson,, E., Kilanowski,, F., Hill,, R. E., … Lettice,, L. A. (2019). Developmentally regulated Shh expression is robust to TAD perturbations. BioRxiv. https://doi.org/10.1101/609941
Williamson,, I., Lettice,, L. A., Hill,, R. E., & Bickmore,, W. A. (2016). Shh and ZRS enhancer colocalisation is specific to the zone of polarising activity. Development, 143(16), 2994–3001. https://doi.org/10.1242/dev.139188
Wu,, C., & Pan,, W. (2018). Integration of enhancer‐promoter interactions with GWAS summary results identifies novel schizophrenia‐associated genes and pathways. Genetics, 209(3), 699–709. https://doi.org/10.1534/genetics.118.300805
Xie,, S., Duan,, J., Li,, B., Zhou,, P., & Hon,, G. C. (2017). Multiplexed engineering and analysis of combinatorial enhancer activity in single cells. Molecular Cell, 66(2), 285–299.e5. https://doi.org/10.1016/j.molcel.2017.03.007
Yang,, D., Xu,, J., Zhu,, T., Fan,, J., Lai,, L., Zhang,, J., & Chen,, Y. E. (2014). Effective gene targeting in rabbits using RNA‐guided Cas9 nucleases. Journal of Molecular Cell Biology, 6(1), 97–99. https://doi.org/10.1093/jmcb/mjt047
Yu,, Z., Ren,, M., Wang,, Z., Zhang,, B., Rong,, Y. S., Jiao,, R., & Gao,, G. (2013). Highly efficient genome modifications mediated by CRISPR/Cas9 in Drosophila. Genetics, 195(1), 289–291. https://doi.org/10.1534/genetics.113.153825
Yuh,, C. H., Ransick,, A., Martinez,, P., Britten,, R. J., & Davidson,, E. H. (1994). Complexity and organization of DNA–protein interactions in the 5′‐regulatory region of an endoderm‐specific marker gene in the sea urchin embryo. Mechanisms of Development, 47, 165–186. https://doi.org/10.1016/0925-4773(94)90088-4
Zabidi,, M. A., Arnold,, C. D., Schernhuber,, K., Pagani,, M., Rath,, M., Frank,, O., & Stark,, A. (2015). Enhancer‐core‐promoter specificity separates developmental and housekeeping gene regulation. Nature, 518, 556–559. https://doi.org/10.1038/nature13994
Zandvakili,, A., Campbell,, I., Gutzwiller,, L. M., Weirauch,, M. T., & Gebelein,, B. (2018). Degenerate Pax2 and senseless binding motifs improve detection of low‐affinity sites required for enhancer specificity. PLoS Genetics, 14(4), e1007289. https://doi.org/10.1371/journal.pgen.1007289
Zaret,, K. S., & Carroll,, J. S. (2011). Pioneer transcription factors: Establishing competence for gene expression. Genes and Development, 25(21), 2227–2241. https://doi.org/10.1101/gad.176826.111
Zhang,, Y., Li,, T., Preissl,, S., Amaral,, M. L., Grinstein,, J. D., Farah,, E. N., … Ren,, B. (2019). Transcriptionally active HERV‐H retrotransposons demarcate topologically associating domains in human pluripotent stem cells. Nature Genetics, 51, 1380–1388. https://doi.org/10.1038/s41588-019-0479-7
Zheng,, M., Tian,, S. Z., Capurso,, D., Kim,, M., Maurya,, R., Lee,, B., … Ruan,, Y. (2019). Multiplex chromatin interactions with single‐molecule precision. Nature, 566, 558–562. https://doi.org/10.1038/s41586-019-0949-1
Zuin,, J., Dixon,, J. R., van der Reijden,, M. I. J. A., Ye,, Z., Kolovos,, P., Brouwer,, R. W. W., … Wendt,, K. S. (2014). Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells. Proceedings of the National Academy of Sciences, 111(3), 996–1001. https://doi.org/10.1073/pnas.1317788111

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

Functional genomic approaches to elucidate the role of enhancers during development

Browse by Topic

Access to this WIREs title is by subscription only.

The latest WIREs articles in your inbox