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Cell. 2015 Aug 27;162(5):1039-50. doi: 10.1016/j.cell.2015.08.001. Epub 2015 Aug 20.

Population Variation and Genetic Control of Modular Chromatin Architecture in Humans.

Author information

1
Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland; Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland.
2
Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland; Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 1211, Switzerland; Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva 1211, Switzerland.
3
Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland; Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne 1015, Switzerland.
4
Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
5
Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne 1015, Switzerland.
6
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 1211, Switzerland.
7
Protein Expression Core Facility, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
8
Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland; Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland. Electronic address: bart.deplancke@epfl.ch.
9
Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland; Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 1211, Switzerland; Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva 1211, Switzerland. Electronic address: emmanouil.dermitzakis@unige.ch.

Abstract

Chromatin state variation at gene regulatory elements is abundant across individuals, yet we understand little about the genetic basis of this variability. Here, we profiled several histone modifications, the transcription factor (TF) PU.1, RNA polymerase II, and gene expression in lymphoblastoid cell lines from 47 whole-genome sequenced individuals. We observed that distinct cis-regulatory elements exhibit coordinated chromatin variation across individuals in the form of variable chromatin modules (VCMs) at sub-Mb scale. VCMs were associated with thousands of genes and preferentially cluster within chromosomal contact domains. We mapped strong proximal and weak, yet more ubiquitous, distal-acting chromatin quantitative trait loci (cQTL) that frequently explain this variation. cQTLs were associated with molecular activity at clusters of cis-regulatory elements and mapped preferentially within TF-bound regions. We propose that local, sequence-independent chromatin variation emerges as a result of genetic perturbations in cooperative interactions between cis-regulatory elements that are located within the same genomic domain.

PMID:
26300124
DOI:
10.1016/j.cell.2015.08.001
[Indexed for MEDLINE]
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