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WIREs Syst Biol Med
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CRISPR/Cas9 genome editing throws descriptive 3‐D genome folding studies for a loop

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CRISPR/Cas9 genome editing studies have recently shed new light into the causal link between the linear DNA sequence and 3‐D chromatin architecture. Here we describe current models for the folding of genomes into a nested hierarchy of higher‐order structures and discuss new insights into the organizing principles governing genome folding at each length scale. WIREs Syst Biol Med 2016, 8:286–299. doi: 10.1002/wsbm.1338 This article is categorized under: Biological Mechanisms > Cell Fates Developmental Biology > Developmental Processes in Health and Disease Laboratory Methods and Technologies > Genetic/Genomic Methods
Diagram of hierarchical genome organization, ranging through the length scales of: (a) DNA wrapped around nucleosomes, (b) looping interactions, (c) sub‐topologically associating domains (sub‐TADs), (d) TADs, (e) A/B compartments, (f) chromosome territories, and (g) the nucleus.
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Topologically associating domain (TAD) border disruption can lead to developmental disorders. (a) Depiction of improper enhancer‐gene interactions that result from TAD boundary disruptions in models of three human limb malformation phenotypes. (b) Representative heatmaps of projected TAD rearrangements in the three limb malformation phenotypes, based on data presented by Lupianez et al. 2015. The linear genome is drawn along the bottom of each heatmap. The interaction frequency between two chromatin fragments is depicted by a colored square at the intersection of diagonal lines originating from each fragment. Interaction frequency ranges from white (low) to dark red (high). TADs appear as large triangles. (Figure adapted from data in Lupianez et al. 2015.)
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Model of gene regulation within sub‐topologically associating domains (sub‐TADs). (a) CTCF binding site deletion leads to inappropriate enhancer‐gene interactions and an ectopic increase in gene expression. (b) When two CTCF binding sites appear between the queried enhancer and nearest gene, deletion of a single CTCF site does not affect gene expression. (c) When both CTCF binding sites are deleted, the off‐target gene is upregulated. Figure adapted from data presented in Dowen et al. 2014.
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CCCTC binding factor (CTCF) binding orientation influences local chromatin architecture. (a) CTCF's 11 zinc‐fingers bind distinct DNA sequences within the canonical CTCF binding motifs, resulting in CTCF engaging with the genome in specific directions depending on the underlying sequence. (b) The four combinations of ‘direction’ that two CTCF motifs along the same DNA strand can occupy are displayed. The majority of CTCF motif pairs that form significant three‐dimensional interactions are in the ‘convergent’ orientation. (c) Representative diagram of changes in chromatin interactions upon deletion/inversion of CTCF binding sites, based on data presented by Guo et al. Significant interactions are represented as green arches.
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Representative heatmaps of chromatin interaction data at different length scales and resolutions. Interaction frequency (B) sub‐TADs, (C) TADS, (D) compartments, (E) chromosomes is depicted on color scale ranging from white (low) to dark red (high). Heatmaps are depicted for the following organizational units: (a) looping interactions, (b) sub‐TADs, (c) TADS, (d) compartments, (e) chromosomes.
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Laboratory Methods and Technologies > Genetic/Genomic Methods
Biological Mechanisms > Cell Fates
Developmental Biology > Developmental Processes in Health and Disease

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