Essential contributions of enhancer genomic regulatory elements to microglial cell identity and functions

Focus Article

André Machado Xavier, Sarah Belhocine, David Gosselin

Published Online: Apr 23 2019

DOI: 10.1002/wsbm.1449

Full article on Wiley Online Library: HTML PDF

Can't access this content? Tell your librarian.

Abstract Microglia are the specialized macrophages of the brain and play essential roles in ensuring its proper functioning. Accumulating evidence suggests that these cells coordinate the inflammatory response that accompanies various clinical brain conditions, including neurodegenerative diseases and psychiatric disorders. Therefore, investigating the functions of these cells and how these are regulated have become important areas of research in neuroscience over the past decade. In this regards, recent efforts to characterize the epigenomic mechanisms underlying microglial gene transcription have provided significant insights into the mechanisms that control the ontogeny and the cellular competences of microglia. In particular, these studies have established that a substantial proportion of the microglial repertoire of promoter‐distal genomic regulatory elements, or enhancers, is relatively specific to these cells compared to other tissue‐resident macrophages. Notably, this specificity is under the regulation of factors present in the brain that modulate activity of target axes of signaling pathways—transcription factors in microglia. Thus, the microglial enhancer repertoire is highly responsive to perturbations in the cerebral tissue microenvironment and this responsiveness has profound implications on the activity of these cells in brain diseases. This article is categorized under: Physiology > Mammalian Physiology in Health and Disease Models of Systems Properties and Processes > Mechanistic Models Biological Mechanisms > Cell Fates Developmental Biology > Lineages

Microglial gene signatures are coupled to brain physiological states. Under healthy brain condition, genes involved in microglial homeostatic cell activity are highly transcribed. Notably, many of those genes are relatively highly expressed compared to other tissue‐resident macrophage subsets and make‐up the microglial transcriptional signature. However, in contexts of lesions, this homeostatic gene signature diminishes. Alternatively, disease‐associated microglia, or DAM, up‐regulate genes that are intrinsically linked to inflammation which enable these cells to acquire new inflammatory functions. Depending upon the type of insult, the inflammatory activity of microglia may be beneficial (e.g., elimination of infectious agents) or detrimental (e.g., chronic inflammatory activity of microglia, as is the case with neurodegenerative diseases)

[ Normal View | Magnified View ]

The microglial enhancer repertoire includes both primed and activated regulatory elements. H3K4me2 and H3K27ac ChIP‐seq data visualization in the vicinity of the mouse Ccr3, Ccr2, and Ccr5 gene loci. H3K4me2 peaks (top track) enables identification of regulatory elements, including promoters and enhancers, that are active or primed for activation. Transcriptional start sites (arrows) allows for identification of protein‐coding gene promoters. Alternatively, assessment of H3K27ac levels (bottom track) enables identification of active regulatory elements. Note that not all H3K4me2^High regions are abundant for H3K27ac

[ Normal View | Magnified View ]

The hierarchal and collaborative model of macrophage enhancer selection. (a) In absence of macrophage lineage‐determining transcription factors (LDTFs), DNA interacts tightly with nucleosomes, which inhibits interactions of signal‐dependent transcription factors (SDTFs) like NF‐κB with their DNA motifs. (b) As macrophage progenitors develop and differentiate, gene encoding LDTFs, including Pu.1, C/ebp and AP‐1 factors, become up‐regulated. In turn, these factors recognize and interact with their DNA motifs, which causes local nucleosomal rearrangement and recruitment of methyltransferases that will modify nearby nucleosomes (e.g., H3K4me1), thus setting up enhancers. Note, however, that certain parameters influence the ability of LDTFs to select enhancers; for example, LDTF motifs that are too far apart will not favor local LDTF activity. (c) Activated SDTFs can bind their motifs at primed enhancers, and this leads to gains in acetylation at nearby nucleosomes (e.g., H3K27ac). Activated enhancers then relay regulatory input from SDTFs to the transcriptional machinery at transcriptional start site of protein‐coding genes (not depicted)

[ Normal View | Magnified View ]

Brain‐derived factors activate signal‐dependent transcription factors that collaborate with Pu.1 to configure the microglial enhancer landscape that underlies their transcriptional signature. (A) Factors present in the brain microenvironment regulate activity of SDTFs that activate pre‐established enhancers to promote a first wave of gene transcription (B). (C) These include, among others, transcription factors that in turn can also collaborate with Pu.1 to set‐up new enhancers which further refine the transcriptional output of the microglial cells (D)

[ Normal View | Magnified View ]

Combination of cellular origin and developmental history enables optimal microglia cell ontogeny. Putative microglia are derived from yolk‐sac progenitors that seed the developing brain early during embryonic development. Therefore, these progenitors/early microglia are necessarily exposed to all the factors that are required for brain development and functions. These factors act in combination to activate signaling pathways in the developing microglial cell population and this enables these cells to achieve their full canonical transcriptional signature. Similarly, cells derived from definitive hematopoiesis, including monocytes, can engraft in the parenchymal brain under defined conditions and acquire some phenotypic traits associated with microglia, including the deployment of an elaborate array of ramifications. However, although the gene expression program of these monocyte‐derived microglia exhibits similarities with that of microglia, it never achieves full duplication. Whether this limitation on transcriptional plasticity arises from timing of their engraftment in the brain, which occurs outside of the development period, or because of different cellular ontological process is currently not known

[ Normal View | Magnified View ]

References

Alliot,, F., Godin,, I., & Pessac,, B. (1999). Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Research. Developmental Brain Research, 117(2), 145–152.
Askew,, K., Li,, K., Olmos‐Alonso,, A., Garcia‐Moreno,, F., Liang,, Y., Richardson,, P., … Gomez‐Nicola,, D. (2017). Coupled proliferation and apoptosis maintain the rapid turnover of microglia in the adult brain. Cell Reports, 18(2), 391–405. https://doi.org/10.1016/j.celrep.2016.12.041
Ayata,, P., Badimon,, A., Strasburger,, H. J., Duff,, M. K., Montgomery,, S. E., Loh,, Y. E., … Schaefer,, A. (2018). Epigenetic regulation of brain region‐specific microglia clearance activity. Nature Neuroscience, 21(8), 1049–1060. https://doi.org/10.1038/s41593-018-0192-3
Aziz,, A., Soucie,, E., Sarrazin,, S., & Sieweke,, M. H. (2009). MafB/c‐Maf deficiency enables self‐renewal of differentiated functional macrophages. Science, 326(5954), 867–871. https://doi.org/10.1126/science.1176056
Bakri,, Y., Sarrazin,, S., Mayer,, U. P., Tillmanns,, S., Nerlov,, C., Boned,, A., & Sieweke,, M. H. (2005). Balance of MafB and PU.1 specifies alternative macrophage or dendritic cell fate. Blood, 105(7), 2707–2716. https://doi.org/10.1182/blood-2004-04-1448
Barozzi,, I., Simonatto,, M., Bonifacio,, S., Yang,, L., Rohs,, R., Ghisletti,, S., & Natoli,, G. (2014). Coregulation of transcription factor binding and nucleosome occupancy through DNA features of mammalian enhancers. Molecular Cell, 54(5), 844–857. https://doi.org/10.1016/j.molcel.2014.04.006
Bennett,, F. C., Bennett,, M. L., Yaqoob,, F., Mulinyawe,, S. B., Grant,, G. A., Hayden Gephart,, M., … Barres,, B. A. (2018). A combination of ontogeny and CNS environment establishes microglial identity. Neuron, 98(6), 1170–1183. https://doi.org/10.1016/j.neuron.2018.05.014
Bohlen,, C. J., Bennett,, F. C., Tucker,, A. F., Collins,, H. Y., Mulinyawe,, S. B., & Barres,, B. A. (2017). Diverse requirements for microglial survival, specification, and function revealed by defined‐medium cultures. Neuron, 94(4), 759–773. https://doi.org/10.1016/j.neuron.2017.04.043
Butovsky,, O., Jedrychowski,, M. P., Moore,, C. S., Cialic,, R., Lanser,, A. J., Gabriely,, G., … Weiner,, H. L. (2014). Identification of a unique TGF‐beta‐dependent molecular and functional signature in microglia. Nature Neuroscience, 17(1), 131–143. https://doi.org/10.1038/nn.3599
Buttgereit,, A., Lelios,, I., Yu,, X., Vrohlings,, M., Krakoski,, N. R., Gautier,, E. L., … Greter,, M. (2016). Sall1 is a transcriptional regulator defining microglia identity and function. Nature Immunology, 17(12), 1397–1406. https://doi.org/10.1038/ni.3585
Creyghton,, M. P., Cheng,, A. W., Welstead,, G. G., Kooistra,, T., Carey,, B. W., Steine,, E. J., … Jaenisch,, R. (2010). Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proceedings of the National Academy of Sciences of the United States of America, 107(50), 21931–21936. https://doi.org/10.1073/pnas.1016071107
Cronk,, J. C., Filiano,, A. J., Louveau,, A., Marin,, I., Marsh,, R., Ji,, E., … Kipnis,, J. (2018). Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia. The Journal of Experimental Medicine, 215(6), 1627–1647. https://doi.org/10.1084/jem.20180247
Datta,, M., Staszewski,, O., Raschi,, E., Frosch,, M., Hagemeyer,, N., Tay,, T. L., … Prinz,, M. (2018). Histone deacetylases 1 and 2 regulate microglia function during development, homeostasis, and neurodegeneration in a context‐dependent manner. Immunity, 48(3), 514–529. https://doi.org/10.1016/j.immuni.2018.02.016
Davalos,, D., Grutzendler,, J., Yang,, G., Kim,, J. V., Zuo,, Y., Jung,, S., … Gan,, W. B. (2005). ATP mediates rapid microglial response to local brain injury in vivo. Nature Neuroscience, 8(6), 752–758. https://doi.org/10.1038/nn1472
Deczkowska,, A., Matcovitch‐Natan,, O., Tsitsou‐Kampeli,, A., Ben‐Hamo,, S., Dvir‐Szternfeld,, R., Spinrad,, A., … Schwartz,, M. (2017). Mef2C restrains microglial inflammatory response and is lost in brain ageing in an IFN‐I‐dependent manner. Nature Communications, 8(1), 717. https://doi.org/10.1038/s41467-017-00769-0
Dor,, Y., & Cedar,, H. (2018). Principles of DNA methylation and their implications for biology and medicine. Lancet, 392(10149), 777–786. https://doi.org/10.1016/S0140-6736(18)31268-6
Elmore,, M. R., Najafi,, A. R., Koike,, M. A., Dagher,, N. N., Spangenberg,, E. E., Rice,, R. A., … Green,, K. N. (2014). Colony‐stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron, 82(2), 380–397. https://doi.org/10.1016/j.neuron.2014.02.040
Fourgeaud,, L., Traves,, P. G., Tufail,, Y., Leal‐Bailey,, H., Lew,, E. D., Burrola,, P. G., … Lemke,, G. (2016). TAM receptors regulate multiple features of microglial physiology. Nature, 532(7598), 240–244. https://doi.org/10.1038/nature17630
Fuger,, P., Hefendehl,, J. K., Veeraraghavalu,, K., Wendeln,, A. C., Schlosser,, C., Obermuller,, U., … Jucker,, M. (2017). Microglia turnover with aging and in an Alzheimer`s model via long‐term in vivo single‐cell imaging. Nature Neuroscience, 20(10), 1371–1376. https://doi.org/10.1038/nn.4631
Fukaya,, T., Lim,, B., & Levine,, M. (2016). Enhancer control of transcriptional bursting. Cell, 166(2), 358–368. https://doi.org/10.1016/j.cell.2016.05.025
Gandal,, M. J., Zhang,, P., Hadjimichael,, E., Walker,, R. L., Chen,, C., Liu,, S., … Geschwind,, D. H. (2018). Transcriptome‐wide isoform‐level dysregulation in ASD, schizophrenia, and bipolar disorder. Science, 362(6420), eaat8127. https://doi.org/10.1126/science.aat8127
Gautier,, E. L., Shay,, T., Miller,, J., Greter,, M., Jakubzick,, C., Ivanov,, S., … Immunological Genome,, C. (2012). Gene‐expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nature Immunology, 13(11), 1118–1128. https://doi.org/10.1038/ni.2419
Ghisletti,, S., Barozzi,, I., Mietton,, F., Polletti,, S., De Santa,, F., Venturini,, E., … Natoli,, G. (2010). Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. Immunity, 32(3), 317–328. https://doi.org/10.1016/j.immuni.2010.02.008
Ginhoux,, F., Greter,, M., Leboeuf,, M., Nandi,, S., See,, P., Gokhan,, S., … Merad,, M. (2010). Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science, 330(6005), 841–845. https://doi.org/10.1126/science.1194637
Glass,, C. K., & Natoli,, G. (2016). Molecular control of activation and priming in macrophages. Nature Immunology, 17(1), 26–33. https://doi.org/10.1038/ni.3306
Goldmann,, T., Wieghofer,, P., Jordao,, M. J., Prutek,, F., Hagemeyer,, N., Frenzel,, K., … Prinz,, M. (2016). Origin, fate and dynamics of macrophages at central nervous system interfaces. Nature Immunology, 17(7), 797–805. https://doi.org/10.1038/ni.3423
Goldmann,, T., Zeller,, N., Raasch,, J., Kierdorf,, K., Frenzel,, K., Ketscher,, L., … Prinz,, M. (2015). USP18 lack in microglia causes destructive interferonopathy of the mouse brain. The EMBO Journal, 34(12), 1612–1629. https://doi.org/10.15252/embj.201490791
Goldstein,, I., & Hager,, G. L. (2018). Dynamic enhancer function in the chromatin context. Wiley Interdisciplinary Reviews. Systems Biology and Medicine, 10(1), 1–10. https://doi.org/10.1002/wsbm.1390
Gomez Perdiguero,, E., Klapproth,, K., Schulz,, C., Busch,, K., Azzoni,, E., Crozet,, L., … Rodewald,, H. R. (2015). Tissue‐resident macrophages originate from yolk‐sac‐derived erythro‐myeloid progenitors. Nature, 518(7540), 547–551. https://doi.org/10.1038/nature13989
Gosselin,, D., Link,, V. M., Romanoski,, C. E., Fonseca,, G. J., Eichenfield,, D. Z., Spann,, N. J., … Glass,, C. K. (2014). Environment drives selection and function of enhancers controlling tissue‐specific macrophage identities. Cell, 159(6), 1327–1340. https://doi.org/10.1016/j.cell.2014.11.023
Gosselin,, D., Skola,, D., Coufal,, N. G., Holtman,, I. R., Schlachetzki,, J. C. M., Sajti,, E., … Glass,, C. K. (2017). An environment‐dependent transcriptional network specifies human microglia identity. Science, 356(6344), eaal3222. https://doi.org/10.1126/science.aal3222
Grabert,, K., Michoel,, T., Karavolos,, M. H., Clohisey,, S., Baillie,, J. K., Stevens,, M. P., … McColl,, B. W. (2016). Microglial brain region‐dependent diversity and selective regional sensitivities to aging. Nature Neuroscience, 19(3), 504–516. https://doi.org/10.1038/nn.4222
Hagemeyer,, N., Kierdorf,, K., Frenzel,, K., Xue,, J., Ringelhan,, M., Abdullah,, Z., … Prinz,, M. (2016). Transcriptome‐based profiling of yolk sac‐derived macrophages reveals a role for Irf8 in macrophage maturation. The EMBO Journal, 35(16), 1730–1744. https://doi.org/10.15252/embj.201693801
Hammond,, T. R., Dufort,, C., Dissing‐Olesen,, L., Giera,, S., Young,, A., Wysoker,, A., … Stevens,, B. (2018). Single‐cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell‐state changes. Immunity, 50, 253–271. https://doi.org/10.1016/j.immuni.2018.11.004
Hammond,, T. R., Robinton,, D., & Stevens,, B. (2018). Microglia and the brain: Complementary partners in development and disease. Annual Review of Cell and Developmental Biology, 34, 523–544. https://doi.org/10.1146/annurev-cellbio-100616-060509
Hanisch,, U. K., & Kettenmann,, H. (2007). Microglia: Active sensor and versatile effector cells in the normal and pathologic brain. Nature Neuroscience, 10(11), 1387–1394. https://doi.org/10.1038/nn1997
Hashimoto,, D., Chow,, A., Noizat,, C., Teo,, P., Beasley,, M. B., Leboeuf,, M., … Merad,, M. (2013). Tissue‐resident macrophages self‐maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity, 38(4), 792–804. https://doi.org/10.1016/j.immuni.2013.04.004
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
Heinz,, S., Benner,, C., Spann,, N., Bertolino,, E., Lin,, Y. C., Laslo,, P., … Glass,, C. K. (2010). Simple combinations of lineage‐determining transcription factors prime cis‐regulatory elements required for macrophage and B cell identities. Molecular Cell, 38(4), 576–589. https://doi.org/10.1016/j.molcel.2010.05.004
Heinz,, S., Romanoski,, C. E., Benner,, C., Allison,, K. A., Kaikkonen,, M. U., Orozco,, L. D., & Glass,, C. K. (2013). Effect of natural genetic variation on enhancer selection and function. Nature, 503(7477), 487–492. https://doi.org/10.1038/nature12615
Heinz,, S., Romanoski,, C. E., Benner,, C., & Glass,, C. K. (2015). The selection and function of cell type‐specific enhancers. Nature Reviews. Molecular Cell Biology, 16(3), 144–154. https://doi.org/10.1038/nrm3949
Hong,, S., Beja‐Glasser,, V. F., Nfonoyim,, B. M., Frouin,, A., Li,, S., Ramakrishnan,, S., … Stevens,, B. (2016). Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science, 352(6286), 712–716. https://doi.org/10.1126/science.aad8373
Horiuchi,, M., Wakayama,, K., Itoh,, A., Kawai,, K., Pleasure,, D., Ozato,, K., & Itoh,, T. (2012). Interferon regulatory factor 8/interferon consensus sequence binding protein is a critical transcription factor for the physiological phenotype of microglia. Journal of Neuroinflammation, 9, 227. https://doi.org/10.1186/1742-2094-9-227
Hoshiko,, M., Arnoux,, I., Avignone,, E., Yamamoto,, N., & Audinat,, E. (2012). Deficiency of the microglial receptor CX3CR1 impairs postnatal functional development of thalamocortical synapses in the barrel cortex. The Journal of Neuroscience, 32(43), 15106–15111. https://doi.org/10.1523/JNEUROSCI.1167-12.2012
Jones,, P. A. (2012). Functions of DNA methylation: Islands, start sites, gene bodies and beyond. Nature Reviews. Genetics, 13(7), 484–492. https://doi.org/10.1038/nrg3230
Jonsson,, T., Stefansson,, H., Steinberg,, S., Jonsdottir,, I., Jonsson,, P. V., Snaedal,, J., … Stefansson,, K. (2013). Variant of TREM2 associated with the risk of Alzheimer`s disease. The New England Journal of Medicine, 368(2), 107–116. https://doi.org/10.1056/NEJMoa1211103
Jordao,, M. J. C., Sankowski,, R., Brendecke,, S. M., Sagar,, Locatelli,, G., Tai,, Y. H., … Prinz,, M. (2019). Single‐cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation. Science, 363(6425), eaat7554. https://doi.org/10.1126/science.aat7554
Kaikkonen,, M. U., Spann,, N. J., Heinz,, S., Romanoski,, C. E., Allison,, K. A., Stender,, J. D., … Glass,, C. K. (2013). Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. Molecular Cell, 51(3), 310–325. https://doi.org/10.1016/j.molcel.2013.07.010
Keren‐Shaul,, H., Spinrad,, A., Weiner,, A., Matcovitch‐Natan,, O., Dvir‐Szternfeld,, R., Ulland,, T. K., … Amit,, I. (2017). A unique microglia type associated with restricting development of Alzheimer`s disease. Cell, 169(7), 1276–1290. https://doi.org/10.1016/j.cell.2017.05.018
Kierdorf,, K., Erny,, D., Goldmann,, T., Sander,, V., Schulz,, C., Perdiguero,, E. G., … Prinz,, M. (2013). Microglia emerge from erythromyeloid precursors via Pu.1‐ and Irf8‐dependent pathways. Nature Neuroscience, 16(3), 273–280. https://doi.org/10.1038/nn.3318
Klemm,, S. L., Shipony,, Z., & Greenleaf,, W. J. (2019). Chromatin accessibility and the regulatory epigenome. Nature Reviews Genetics, 20(4), 207–220. https://doi.org/10.1038/s41576-018-0089-8
Krasemann,, S., Madore,, C., Cialic,, R., Baufeld,, C., Calcagno,, N., El Fatimy,, R., … Butovsky,, O. (2017). The TREM2‐APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity, 47(3), 566–581. https://doi.org/10.1016/j.immuni.2017.08.008
Lampron,, A., Larochelle,, A., Laflamme,, N., Prefontaine,, P., Plante,, M. M., Sanchez,, M. G., … Rivest,, S. (2015). Inefficient clearance of myelin debris by microglia impairs remyelinating processes. The Journal of Experimental Medicine, 212(4), 481–495. https://doi.org/10.1084/jem.20141656
Larsson,, A. J. M., Johnsson,, P., Hagemann‐Jensen,, M., Hartmanis,, L., Faridani,, O. R., Reinius,, B., … Sandberg,, R. (2019). Genomic encoding of transcriptional burst kinetics. Nature, 565(7738), 251–254. https://doi.org/10.1038/s41586-018-0836-1
Lavin,, Y., Winter,, D., Blecher‐Gonen,, R., David,, E., Keren‐Shaul,, H., Merad,, M., … Amit,, I. (2014). Tissue‐resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell, 159(6), 1312–1326. https://doi.org/10.1016/j.cell.2014.11.018
Lee,, C. Y., & Landreth,, G. E. (2010). The role of microglia in amyloid clearance from the AD brain. Journal of Neural Transmission (Vienna), 117(8), 949–960. https://doi.org/10.1007/s00702-010-0433-4
Li,, Q., Cheng,, Z., Zhou,, L., Darmanis,, S., Neff,, N. F., Okamoto,, J., … Barres,, B. A. (2019). Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single‐cell RNA sequencing. Neuron, 101(2), 207–223. https://doi.org/10.1016/j.neuron.2018.12.006
Link,, V. M., Duttke,, S. H., Chun,, H. B., Holtman,, I. R., Westin,, E., Hoeksema,, M. A., … Glass,, C. K. (2018). Analysis of genetically diverse macrophages reveals local and domain‐wide mechanisms that control transcription factor binding and function. Cell, 173(7), 1796–1809. https://doi.org/10.1016/j.cell.2018.04.018
Lund,, H., Pieber,, M., Parsa,, R., Han,, J., Grommisch,, D., Ewing,, E., … Harris,, R. A. (2018). Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia‐like cells. Nature Communications, 9(1), 4845. https://doi.org/10.1038/s41467-018-07295-7
Lupien,, M., Eeckhoute,, J., Meyer,, C. A., Wang,, Q., Zhang,, Y., Li,, W., … Brown,, M. (2008). FoxA1 translates epigenetic signatures into enhancer‐driven lineage‐specific transcription. Cell, 132(6), 958–970. https://doi.org/10.1016/j.cell.2008.01.018
Ma,, W., Silverman,, S. M., Zhao,, L., Villasmil,, R., Campos,, M. M., Amaral,, J., & Wong,, W. T. (2019). Absence of TGFbeta signaling in retinal microglia induces retinal degeneration and exacerbates choroidal neovascularization. eLife, 8, 1–28. https://doi.org/10.7554/eLife.42049
Makwana,, M., Jones,, L. L., Cuthill,, D., Heuer,, H., Bohatschek,, M., Hristova,, M., … Raivich,, G. (2007). Endogenous transforming growth factor beta 1 suppresses inflammation and promotes survival in adult CNS. The Journal of Neuroscience, 27(42), 11201–11213. https://doi.org/10.1523/JNEUROSCI.2255-07.2007
Mass,, E., Ballesteros,, I., Farlik,, M., Halbritter,, F., Gunther,, P., Crozet,, L., … Geissmann,, F. (2016). Specification of tissue‐resident macrophages during organogenesis. Science, 353(6304), aaf4238. https://doi.org/10.1126/science.aaf4238
Masuda,, T., Sankowski,, R., Staszewski,, O., Bottcher,, C., Amann,, L., Scheiwe,, C., … Prinz,, M. (2019). Spatial and temporal heterogeneity of mouse and human microglia at single‐cell resolution. Nature, 566(7744), 388–392. https://doi.org/10.1038/s41586-019-0924-x
Matcovitch‐Natan,, O., Winter,, D. R., Giladi,, A., Vargas Aguilar,, S., Spinrad,, A., Sarrazin,, S., … Amit,, I. (2016). Microglia development follows a stepwise program to regulate brain homeostasis. Science, 353(6301), aad8670. https://doi.org/10.1126/science.aad8670
Mathys,, H., Adaikkan,, C., Gao,, F., Young,, J. Z., Manet,, E., Hemberg,, M., … Tsai,, L. H. (2017). Temporal tracking of microglia activation in neurodegeneration at single‐cell resolution. Cell Reports, 21(2), 366–380. https://doi.org/10.1016/j.celrep.2017.09.039
Meng,, H., & Bartholomew,, B. (2018). Emerging roles of transcriptional enhancers in chromatin looping and promoter‐proximal pausing of RNA polymerase II. The Journal of Biological Chemistry, 293(36), 13786–13794. https://doi.org/10.1074/jbc.R117.813485
Minten,, C., Terry,, R., Deffrasnes,, C., King,, N. J., & Campbell,, I. L. (2012). IFN regulatory factor 8 is a key constitutive determinant of the morphological and molecular properties of microglia in the CNS. PLoS One, 7(11), e49851. https://doi.org/10.1371/journal.pone.0049851
Nguyen,, M. D., Julien,, J. P., & Rivest,, S. (2002). Innate immunity: The missing link in neuroprotection and neurodegeneration? Nature Reviews. Neuroscience, 3(3), 216–227. https://doi.org/10.1038/nrn752
Nimmerjahn,, A., Kirchhoff,, F., & Helmchen,, F. (2005). Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science, 308(5726), 1314–1318. https://doi.org/10.1126/science.1110647
Okabe,, Y., & Medzhitov,, R. (2014). Tissue‐specific signals control reversible program of localization and functional polarization of macrophages. Cell, 157(4), 832–844. https://doi.org/10.1016/j.cell.2014.04.016
Paolicelli,, R. C., Bolasco,, G., Pagani,, F., Maggi,, L., Scianni,, M., Panzanelli,, P., … Gross,, C. T. (2011). Synaptic pruning by microglia is necessary for normal brain development. Science, 333(6048), 1456–1458. https://doi.org/10.1126/science.1202529
Parkhurst,, C. N., Yang,, G., Ninan,, I., Savas,, J. N., Yates,, J. R., 3rd, Lafaille,, J. J., … Gan,, W. B. (2013). Microglia promote learning‐dependent synapse formation through brain‐derived neurotrophic factor. Cell, 155(7), 1596–1609. https://doi.org/10.1016/j.cell.2013.11.030
Pont‐Lezica,, L., Beumer,, W., Colasse,, S., Drexhage,, H., Versnel,, M., & Bessis,, A. (2014). Microglia shape corpus callosum axon tract fasciculation: Functional impact of prenatal inflammation. The European Journal of Neuroscience, 39(10), 1551–1557. https://doi.org/10.1111/ejn.12508
Poon,, G. M. K., & Kim,, H. M. (2017). Signatures of DNA target selectivity by ETS transcription factors. Transcription, 8(3), 193–203. https://doi.org/10.1080/21541264.2017.1302901
Qin,, Y., Garrison,, B. S., Ma,, W., Wang,, R., Jiang,, A., Li,, J., … Springer,, T. A. (2018). A milieu molecule for TGF‐beta required for microglia function in the nervous system. Cell, 174(1), 156–171. https://doi.org/10.1016/j.cell.2018.05.027
Ransohoff,, R. M., & Cardona,, A. E. (2010). The myeloid cells of the central nervous system parenchyma. Nature, 468(7321), 253–262. https://doi.org/10.1038/nature09615
Ren,, B., & Yue,, F. (2015). Transcriptional enhancers: Bridging the genome and phenome. Cold Spring Harbor Symposia on Quantitative Biology, 80, 17–26. https://doi.org/10.1101/sqb.2015.80.027219
Reu,, P., Khosravi,, A., Bernard,, S., Mold,, J. E., Salehpour,, M., Alkass,, K., … Frisen,, J. (2017). The lifespan and turnover of microglia in the human brain. Cell Reports, 20(4), 779–784. https://doi.org/10.1016/j.celrep.2017.07.004
Rivera,, C. M., & Ren,, B. (2013). Mapping human epigenomes. Cell, 155(1), 39–55. https://doi.org/10.1016/j.cell.2013.09.011
Rivest,, S. (2009). Regulation of innate immune responses in the brain. Nature Reviews. Immunology, 9(6), 429–439. https://doi.org/10.1038/nri2565
Safaiyan,, S., Kannaiyan,, N., Snaidero,, N., Brioschi,, S., Biber,, K., Yona,, S., … Simons,, M. (2016). Age‐related myelin degradation burdens the clearance function of microglia during aging. Nature Neuroscience, 19(8), 995–998. https://doi.org/10.1038/nn.4325
Salter,, M. W., & Stevens,, B. (2017). Microglia emerge as central players in brain disease. Nature Medicine, 23(9), 1018–1027. https://doi.org/10.1038/nm.4397
Schafer,, D. P., Lehrman,, E. K., Kautzman,, A. G., Koyama,, R., Mardinly,, A. R., Yamasaki,, R., … Stevens,, B. (2012). Microglia sculpt postnatal neural circuits in an activity and complement‐dependent manner. Neuron, 74(4), 691–705. https://doi.org/10.1016/j.neuron.2012.03.026
Schulz,, C., Gomez Perdiguero,, E., Chorro,, L., Szabo‐Rogers,, H., Cagnard,, N., Kierdorf,, K., … Geissmann,, F. (2012). A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science, 336(6077), 86–90. https://doi.org/10.1126/science.1219179
Shemer,, A., Grozovski,, J., Tay,, T. L., Tao,, J., Volaski,, A., Süß,, P., … Jung,, S. (2018). Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge. Nature Communications, 9(1), 5206. https://doi.org/10.1038/s41467-018-07548-5
Sierra,, A., Encinas,, J. M., Deudero,, J. J., Chancey,, J. H., Enikolopov,, G., Overstreet‐Wadiche,, L. S., … Maletic‐Savatic,, M. (2010). Microglia shape adult hippocampal neurogenesis through apoptosis‐coupled phagocytosis. Cell Stem Cell, 7(4), 483–495. https://doi.org/10.1016/j.stem.2010.08.014
Sipe,, G. O., Lowery,, R. L., Tremblay,, M. E., Kelly,, E. A., Lamantia,, C. E., & Majewska,, A. K. (2016). Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex. Nature Communications, 7, 10905. https://doi.org/10.1038/ncomms10905
Smith,, E., & Shilatifard,, A. (2014). Enhancer biology and enhanceropathies. Nature Structural %26 Molecular Biology, 21(3), 210–219. https://doi.org/10.1038/nsmb.2784
Smith,, Z. D., & Meissner,, A. (2013). DNA methylation: Roles in mammalian development. Nature Reviews. Genetics, 14(3), 204–220. https://doi.org/10.1038/nrg3354
Soucie,, E. L., Weng,, Z., Geirsdottir,, L., Molawi,, K., Maurizio,, J., Fenouil,, R., … Sieweke,, M. H. (2016). Lineage‐specific enhancers activate self‐renewal genes in macrophages and embryonic stem cells. Science, 351(6274), aad5510. https://doi.org/10.1126/science.aad5510
Sousa,, C., Golebiewska,, A., Poovathingal,, S. K., Kaoma,, T., Pires‐Afonso,, Y., Martina,, S., … Michelucci,, A. (2018). Single‐cell transcriptomics reveals distinct inflammation‐induced microglia signatures. EMBO Reports, 19(11), e46171. https://doi.org/10.15252/embr.201846171
Tay,, T. L., Mai,, D., Dautzenberg,, J., Fernandez‐Klett,, F., Lin,, G., Sagar,, … Prinz,, M. (2017). A new fate mapping system reveals context‐dependent random or clonal expansion of microglia. Nature Neuroscience, 20(6), 793–803. https://doi.org/10.1038/nn.4547
Tozaki‐Saitoh,, H., Masuda,, J., Kawada,, R., Kojima,, C., Yoneda,, S., Masuda,, T., … Tsuda,, M. (2019). Transcription factor MafB contributes to the activation of spinal microglia underlying neuropathic pain development. Glia, 67(4), 729–740. https://doi.org/10.1002/glia.23570
Tremblay,, M. E., Lowery,, R. L., & Majewska,, A. K. (2010). Microglial interactions with synapses are modulated by visual experience. PLoS Biology, 8(11), e1000527. https://doi.org/10.1371/journal.pbio.1000527
Tremblay,, M. E., Stevens,, B., Sierra,, A., Wake,, H., Bessis,, A., & Nimmerjahn,, A. (2011). The role of microglia in the healthy brain. The Journal of Neuroscience, 31(45), 16064–16069. https://doi.org/10.1523/JNEUROSCI.4158-11.2011
Ueno,, M., Fujita,, Y., Tanaka,, T., Nakamura,, Y., Kikuta,, J., Ishii,, M., & Yamashita,, T. (2013). Layer V cortical neurons require microglial support for survival during postnatal development. Nature Neuroscience, 16(5), 543–551. https://doi.org/10.1038/nn.3358
Ulmann,, L., Hirbec,, H., & Rassendren,, F. (2010). P2X4 receptors mediate PGE2 release by tissue‐resident macrophages and initiate inflammatory pain. The EMBO Journal, 29(14), 2290–2300. https://doi.org/10.1038/emboj.2010.126
van der Poel,, M., Ulas,, T., Mizee,, M. R., Hsiao,, C. C., Miedema,, S. S. M., Adelia,, … Huitinga,, I. (2019). Transcriptional profiling of human microglia reveals grey‐white matter heterogeneity and multiple sclerosis‐associated changes. Nature Communications, 10(1), 1139. https://doi.org/10.1038/s41467-019-08976-7
Vogel Ciernia,, A., Careaga,, M., LaSalle,, J. M., & Ashwood,, P. (2018). Microglia from offspring of dams with allergic asthma exhibit epigenomic alterations in genes dysregulated in autism. Glia, 66(3), 505–521. https://doi.org/10.1002/glia.23261
Wang,, X., Zhao,, L., Zhang,, J., Fariss,, R. N., Ma,, W., Kretschmer,, F., … Wong,, W. T. (2016). Requirement for microglia for the maintenance of synaptic function and integrity in the mature retina. The Journal of Neuroscience, 36(9), 2827–2842. https://doi.org/10.1523/JNEUROSCI.3575-15.2016
Wendeln,, A. C., Degenhardt,, K., Kaurani,, L., Gertig,, M., Ulas,, T., Jain,, G., … Neher,, J. J. (2018). Innate immune memory in the brain shapes neurological disease hallmarks. Nature, 556(7701), 332–338. https://doi.org/10.1038/s41586-018-0023-4
Wlodarczyk,, A., Holtman,, I. R., Krueger,, M., Yogev,, N., Bruttger,, J., Khorooshi,, R., … Owens,, T. (2017). A novel microglial subset plays a key role in myelinogenesis in developing brain. The EMBO Journal, 36(22), 3292–3308. https://doi.org/10.15252/embj.201696056
Zaret,, K. S., & Carroll,, J. S. (2011). Pioneer transcription factors: Establishing competence for gene expression. Genes %26 Development, 25(21), 2227–2241. https://doi.org/10.1101/gad.176826.111
Zhang,, B., Gaiteri,, C., Bodea,, L. G., Wang,, Z., McElwee,, J., Podtelezhnikov,, A. A., … Emilsson,, V. (2013). Integrated systems approach identifies genetic nodes and networks in late‐onset Alzheimer`s disease. Cell, 153(3), 707–720. https://doi.org/10.1016/j.cell.2013.03.030
Zhou,, N., Liu,, K., Sun,, Y., Cao,, Y., & Yang,, J. (2018). Transcriptional mechanism of IRF8 and PU.1 governs microglial activation in neurodegenerative condition. Protein %26 Cell, 10, 87–103. https://doi.org/10.1007/s13238-018-0599-3
Zhu,, Y., Sun,, L., Chen,, Z., Whitaker,, J. W., Wang,, T., & Wang,, W. (2013). Predicting enhancer transcription and activity from chromatin modifications. Nucleic Acids Research, 41(22), 10032–10043. https://doi.org/10.1093/nar/gkt826
Zoller,, T., Schneider,, A., Kleimeyer,, C., Masuda,, T., Potru,, P. S., Pfeifer,, D., … Spittau,, B. (2018). Silencing of TGFbeta signalling in microglia results in impaired homeostasis. Nature Communications, 9(1), 4011. https://doi.org/10.1038/s41467-018-06224-y

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

Essential contributions of enhancer genomic regulatory elements to microglial cell identity and functions

Browse by Topic

Access to this WIREs title is by subscription only.

The latest WIREs articles in your inbox