title: Population Variation and Genetic Control of Modular Chromatin Architecture in Humans.
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.
authors: Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland; Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland.
authors: Sebastian M
authors: SM
authors: Waszak
authors: 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.
authors: Olivier
authors: O
authors: Delaneau
authors: Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland; Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne 1015, Switzerland.
authors: Andreas R
authors: AR
authors: Gschwind
authors: 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.
authors: Helena
authors: H
authors: Kilpinen
authors: Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
authors: Sunil K
authors: SK
authors: Raghav
authors: Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne 1015, Switzerland.
authors: Robert M
authors: RM
authors: Witwicki
authors: Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne 1015, Switzerland.
authors: Andrea
authors: A
authors: Orioli
authors: Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne 1015, Switzerland.
authors: Michael
authors: M
authors: Wiederkehr
authors: 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.
authors: Nikolaos I
authors: NI
authors: Panousis
authors: 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.
authors: Alisa
authors: A
authors: Yurovsky
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 1211, Switzerland.
authors: Luciana
authors: L
authors: Romano-Palumbo
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 1211, Switzerland.
authors: Alexandra
authors: A
authors: Planchon
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 1211, Switzerland.
authors: Deborah
authors: D
authors: Bielser
authors: 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.
authors: Ismael
authors: I
authors: Padioleau
authors: Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
authors: Gilles
authors: G
authors: Udin
authors: Protein Expression Core Facility, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
authors: Sarah
authors: S
authors: Thurnheer
authors: Protein Expression Core Facility, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
authors: David
authors: D
authors: Hacker
authors: Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne 1015, Switzerland.
authors: Nouria
authors: N
authors: Hernandez
authors: Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne 1015, Switzerland.
authors: Alexandre
authors: A
authors: Reymond
authors: 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.
authors: Bart
authors: B
authors: Deplancke
authors: 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.
authors: Emmanouil T
authors: ET
authors: Dermitzakis
mesh_terms: D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism; D002877:Chromosomes, Human / Q000737:chemistry; D005786:Gene Expression Regulation; D014644:Genetic Variation; D005828:Genetics, Population; D015894:Genome, Human; D006801:Humans; D040641:Quantitative Trait Loci; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D002843:Chromatin; D014157:Transcription Factors