Patterns of regulatory activity across diverse human cell types predict tissue identity, transcription factor binding, and long-range interactions

Abstract

Regulatory elements recruit transcription factors that modulate gene expression distinctly across cell types, but the relationships among these remains elusive. To address this, we analyzed matched DNase-seq and gene expression data for 112 human samples representing 72 cell types. We first defined more than 1800 clusters of DNase I hypersensitive sites (DHSs) with similar tissue specificity of DNase-seq signal patterns. We then used these to uncover distinct associations between DHSs and promoters, CpG islands, conserved elements, and transcription factor motif enrichment. Motif analysis within clusters identified known and novel motifs in cell-type-specific and ubiquitous regulatory elements and supports a role for AP-1 regulating open chromatin. We developed a classifier that accurately predicts cell-type lineage based on only 43 DHSs and evaluated the tissue of origin for cancer cell types. A similar classifier identified three sex-specific loci on the X chromosome, including the XIST lincRNA locus. By correlating DNase I signal and gene expression, we predicted regulated genes for more than 500K DHSs. Finally, we introduce a web resource to enable researchers to use these results to explore these regulatory patterns and better understand how expression is modulated within and across human cell types.

Human active X-specific DNA methylation events showing stability across time and tissues

“…Our analysis therefore shows that Xa-specific methylation is associated with loss of active histone marks in males at genomic regions that have previously been implicated in sex-specific roles in X inactivation. 34 Therefore, we provide preliminary evidence for a role of DNA methylation on the active X in maintaining sex-specific accessiblechromatin patterns. However, this appears limited to only a few specific loci, and is not a widespread phenomenon.…”

“…Remarkably, LOC286467 was previously identified as the only locus besides XIST with sex-specific RNA polymerase 2 binding, 33 and along with XIST, LOC550643 was the only locus with sex-specific DNAse I hypersensitivity patterns. 34 Unfortunately, the Infinium HM450 array did not cover the gene body of LOC550643, which showed H3K4me3 enrichment in females from the BLUEPRINT data. Our analysis therefore shows that Xa-specific methylation is associated with loss of active histone marks in males at genomic regions that have previously been implicated in sex-specific roles in X inactivation.…”

Bayesian multiple logistic regression for case-control GWAS

“…This situation is the rule rather than the exception, 18 because SNPs are usually stronlgy correlated to dozens of nearby SNPs, up to distances of 100 19 kbp. This non-random correlation between nearby SNPs is referred to as linkage disequilibrium 20 (LD) and occurs due to the common descent of humankind from a relatively small ancestral 21 population.…”

“…To test the ability for using genome-wide functional genomics tracks to 262 help distinguish causal from merely correlated SNPs, we used DNase-seq data to measure DNA 263 accessibility, published by the ENCODE project [10]. We normalized the DNase-seq data for 264 112 human samples, as described previously by Sheffield et al [19].…”

The ubiquitous transcription factor CTCF promotes lineage-specific epigenomic remodeling and establishment of transcriptional networks driving cell differentiation

“…2,23,24 Based on this latter function and on the identification of conserved CTCF binding events across various cell-types and tissues, [25][26][27] this TF was proposed to fulfil a general chromatin organization role. 28 At the same time, specific roles for CTCF in neuronal and haematopoietic cell differentiation had been defined. 29 In this context, detailed analyses of CTCF cistromic studies revealed the existence of cell type-specific chromatin binding sites.…”