Population Variation and Genetic Control of Modular Chromatin Architecture in Humans

Sebastian M Waszak; Olivier Delaneau; Andreas R Gschwind; Helena Kilpinen; Sunil K Raghav; Robert M Witwicki; Andrea Orioli; Michael Wiederkehr; Nikolaos I Panousis; Alisa Yurovsky; Luciana Romano-Palumbo; Alexandra Planchon; Deborah Bielser; Ismael Padioleau; Gilles Udin; Sarah Thurnheer; David Hacker; Nouria Hernandez; Alexandre Reymond; Bart Deplancke; Emmanouil T Dermitzakis

doi:10.1016/j.cell.2015.08.001

Population Variation and Genetic Control of Modular Chromatin Architecture in Humans

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

Authors

Sebastian M Waszak¹, Olivier Delaneau², Andreas R Gschwind³, Helena Kilpinen², Sunil K Raghav⁴, Robert M Witwicki⁵, Andrea Orioli⁵, Michael Wiederkehr⁵, Nikolaos I Panousis², Alisa Yurovsky², Luciana Romano-Palumbo⁶, Alexandra Planchon⁶, Deborah Bielser⁶, Ismael Padioleau², Gilles Udin⁴, Sarah Thurnheer⁷, David Hacker⁷, Nouria Hernandez⁵, Alexandre Reymond⁵, Bart Deplancke⁸, Emmanouil T Dermitzakis⁹

Affiliations

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.

PMID: 26300124
DOI: 10.1016/j.cell.2015.08.001

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Chromatin / chemistry*
Chromatin / metabolism
Chromosomes, Human / chemistry
Gene Expression Regulation*
Genetic Variation*
Genetics, Population
Genome, Human*
Humans
Quantitative Trait Loci
Regulatory Sequences, Nucleic Acid
Transcription Factors / metabolism

Substances

Chromatin
Transcription Factors

Grants and funding

MH101814/MH/NIMH NIH HHS/United States