Computational prediction of CTCF/cohesin-based intra-TAD loops that insulate chromatin contacts and gene expression in mouse liver

ELife
Bryan J Matthews, David J Waxman

Abstract

CTCF and cohesin are key drivers of 3D-nuclear organization, anchoring the megabase-scale Topologically Associating Domains (TADs) that segment the genome. Here, we present and validate a computational method to predict cohesin-and-CTCF binding sites that form intra-TAD DNA loops. The intra-TAD loop anchors identified are structurally indistinguishable from TAD anchors regarding binding partners, sequence conservation, and resistance to cohesin knockdown; further, the intra-TAD loops retain key functional features of TADs, including chromatin contact insulation, blockage of repressive histone mark spread, and ubiquity across tissues. We propose that intra-TAD loops form by the same loop extrusion mechanism as the larger TAD loops, and that their shorter length enables finer regulatory control in restricting enhancer-promoter interactions, which enables selective, high-level expression of gene targets of super-enhancers and genes located within repressive nuclear compartments. These findings elucidate the role of intra-TAD cohesin-and-CTCF binding in nuclear organization associated with widespread insulation of distal enhancer activity.

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Citations

Jun 27, 2019·Toxicological Sciences : an Official Journal of the Society of Toxicology·Andy RampersaudDavid J Waxman
Oct 12, 2019·Scientific Reports·Kamel JabbariThomas Wiehe
Sep 15, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Yea Woon KimAeRi Kim
Dec 8, 2019·Nature Communications·Shilu ZhangSushmita Roy
Dec 7, 2020·Briefings in Bioinformatics·Fu-Ying DaoHao Lin
Dec 16, 2020·Epigenetics : Official Journal of the DNA Methylation Society·Andrew VonHandorfAlvaro Puga
Jan 20, 2021·PLoS Computational Biology·Pedro Manuel Martínez-GarcíaFelipe Cortés-Ledesma
Mar 27, 2021·Trends in Cell Biology·Carlos Perea-ResaMichael D Blower
Jul 23, 2021·Nature Communications·Tatiana L FonsecaAntonio C Bianco

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Datasets Mentioned

BETA
GM12878
cells
GSE102997
GSE102998
GSE102999

Methods Mentioned

BETA
Hi-C
immunoprecipitation
ChIP-seq
ChIP
PCA
single cell Hi-C
Assay
PCR

Software Mentioned

Deeptools
bwa
Hi
Bowtie2
JASPAR
bigWigCorrelate
4Cker
ChIP
analyzeHiC
Pro

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