Chromatin three-dimensional interactions mediate genetic effects on gene expression

O Delaneau; M Zazhytska; C Borel; G Giannuzzi; G Rey; C Howald; S Kumar; H Ongen; K Popadin; D Marbach; G Ambrosini; D Bielser; D Hacker; L Romano; P Ribaux; M Wiederkehr; E Falconnet; P Bucher; S Bergmann; S E Antonarakis; A Reymond; E T Dermitzakis

doi:10.1126/science.aat8266

Chromatin three-dimensional interactions mediate genetic effects on gene expression

Science. 2019 May 3;364(6439):eaat8266. doi: 10.1126/science.aat8266.

Authors

O Delaneau^{1

2

3}, M Zazhytska⁴, C Borel^{1

3}, G Giannuzzi⁴, G Rey^{1

2

3}, C Howald^{1

2

3}, S Kumar^{5

6}, H Ongen^{1

2

3}, K Popadin^{4

6

7}, D Marbach^{8

6}, G Ambrosini^{5

6}, D Bielser¹, D Hacker⁹, L Romano¹, P Ribaux¹, M Wiederkehr⁴, E Falconnet¹, P Bucher^{5

6}, S Bergmann^{6

8

10}, S E Antonarakis^#^{1

3}, A Reymond^#¹¹, E T Dermitzakis^#^{2

3

12}

Affiliations

¹ Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
² Swiss Institute of Bioinformatics (SIB), University of Geneva, Geneva, Switzerland.
³ Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland.
⁴ Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
⁵ Swiss Institute for Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
⁶ Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
⁷ School of Life Science, Immanuel Kant Federal Baltic University, Kaliningrad, Russia.
⁸ Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
⁹ Protein Expression Core Facility, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
¹⁰ Computational Biology Division N1.05, Werner Beit North Faculty of Health Sciences, Cape Town, South Africa.
¹¹ Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. [email protected]
¹² Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland. [email protected]

^# Contributed equally.

PMID: 31048460
DOI: 10.1126/science.aat8266

Abstract

Studying the genetic basis of gene expression and chromatin organization is key to characterizing the effect of genetic variability on the function and structure of the human genome. Here we unravel how genetic variation perturbs gene regulation using a dataset combining activity of regulatory elements, gene expression, and genetic variants across 317 individuals and two cell types. We show that variability in regulatory activity is structured at the intra- and interchromosomal levels within 12,583 cis-regulatory domains and 30 trans-regulatory hubs that highly reflect the local (that is, topologically associating domains) and global (that is, open and closed chromatin compartments) nuclear chromatin organization. These structures delimit cell type-specific regulatory networks that control gene expression and coexpression and mediate the genetic effects of cis- and trans-acting regulatory variants on genes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Chromatin / chemistry
Chromatin / metabolism*
Gene Expression Regulation*
Genetic Variation
Genome, Human
Humans
Quantitative Trait Loci
Regulatory Elements, Transcriptional

Substances

Chromatin

Grants and funding

European Research Council/International