Match!

Chromatin three-dimensional interactions mediate genetic effects on gene expression

Published on May 3, 2019in Science41.04
· DOI :10.1126/science.aat8266
Olivier Delaneau26
Estimated H-index: 26
(Swiss Institute of Bioinformatics),
M. Zazhytska3
Estimated H-index: 3
(UNIL: University of Lausanne)
+ 19 AuthorsEmmanouil T. Dermitzakis80
Estimated H-index: 80
(Swiss Institute of Bioinformatics)
Abstract
INTRODUCTION Genome-wide studies on the genetic basis of gene expression have advanced considerably our understanding of the function of the human genome. Large collections of expression quantitative trait loci (i.e., genetic variations affecting gene expression; eQTLs) are now available across many cell types, tissues, and conditions and are commonly used to better interpret the effects of noncoding genetic variations. Although this constitutes an extraordinary resource to study complex organismal traits and diseases, we still have a poor understanding of how they affect the regulatory machinery, which regulatory elements (REs) they perturb, and how their effects propagate along regulatory interactions. RATIONALE In this study, we aimed to characterize the complex and cell type–specific interplay between genetic variation, REs, and gene expression to dissect cis- and trans-regulatory coordination. To this end, we assembled and analyzed a population-scale dataset combining the activity of REs [measured by chromatin immunoprecipitation sequencing (ChIP-seq) for methylated histone 3 at lysine 4 (H3K4me1), trimethylated histone 3 at lysine 4 (H3K4me3), and acetylated histone 3 at lysine 27 (H3K27ac)], the expression of genes (using RNA-seq), and genetic variations for 317 lymphoblastoid and 78 fibroblast cell lines, all from European ancestry. RESULTS First, we show that the regulatory activity is structured in 12,583 well-delimited cis-regulatory domains (CRDs) that respect the local chromatin organization into topologically associating domains (TADs) but constitute finer organization. Our work suggests that three-dimensional (3D) organization in cis can be broadly categorized into functionally linked and unlinked domains, with the most-linked ones corresponding to CRDs. In addition, we found 25,315 significant associations between CRDs located on distinct chromosomes that form 30 trans-regulatory hubs (TRHs). These TRHs are consistent with a higher-order chromatin organization into A and B nuclear compartments and show a signal of allelic coordination, suggesting that some of the trans associations are not transcriptionally mediated and result from a complex and higher-order 3D nucleus organization. Second, we show that CRDs and TRHs essentially delimit sets of active REs involved in the expression of most genes and provide a dense genome-wide map linking REs and genes. We show that these links vary substantially across cell types and are key factors involved in the cis and trans coexpression of genes. Third, we show that CRDs are under strong genetic control. We discovered a total of 58,968 chromatin peaks affected by nearby genetic variants (cQTLs), 6157 QTLs that affect the activity of CRDs (aCRD-QTLs), and 110 QTLs that affect the correlation structure within CRDs (sCRD-QTLs). These QTLs tend to locate close to their genomic targets, are enriched within functional regions of the genome, and frequently overlap genetic variants associated with complex traits. Finally, we show that CRDs and TRHs capture complex regulatory networks along which the effects of eQTLs are propagated and synergized to affect gene expression. Overall, we estimate that 75% of the eQTLs also affect the activity of CRDs and describe four specific types of genetic effects that can be mediated by CRDs: (i) cis-eQTLs affecting distal genes, (ii) multiple cis-eQTLs with independent effects, (iii) multiple rare variants that have a cumulative effect, and (iv) trans-eQTLs. CONCLUSION We provide a genome-wide map of the coordination between REs and describe how this serves as a backbone for the propagation of noncoding genetic effects in cis and trans onto gene expression. We show how these types of data can reveal higher-order functional attributes of the genome and can serve as an effective prior to boost future association studies at both the discovery and interpretation levels. Overall, our study reveals the complexity and specificity of the cis- and trans-regulatory circuitry and its perturbation by genetic variations.
  • References (61)
  • Citations (4)
References61
Newest
#1Kevin Monahan (Columbia University)H-Index: 7
#2Adan Horta (Columbia University)H-Index: 2
Last.Stavros Lomvardas (Columbia University)H-Index: 22
view all 3 authors...
#1Rachel E. Gate (UCSF: University of California, San Francisco)H-Index: 8
#2Christine S. Cheng (Broad Institute)H-Index: 11
Last.Aviv Regev (MIT: Massachusetts Institute of Technology)H-Index: 98
view all 22 authors...
#1Benjamin R. Sabari (MIT: Massachusetts Institute of Technology)H-Index: 8
#2Alessandra Dall’Agnese (MIT: Massachusetts Institute of Technology)H-Index: 4
Last.John Colonnese Manteiga (MIT: Massachusetts Institute of Technology)H-Index: 3
view all 23 authors...
#1Lead analysts (Swiss Institute of Bioinformatics)H-Index: 2
#2Alexis Battle (Johns Hopkins University)H-Index: 27
Last.Stephen B. Montgomery (Stanford University)H-Index: 44
view all 5 authors...
#1Alexandre Fort (University of Geneva)H-Index: 10
#2Nikolaos Panousis (Swiss Institute of Bioinformatics)H-Index: 8
Last.Olivier Delaneau (Swiss Institute of Bioinformatics)H-Index: 26
view all 7 authors...
#1Paula Freire-Pritchett (Babraham Institute)H-Index: 5
#2Stefan Schoenfelder (Babraham Institute)H-Index: 21
Last.Peter Fraser (Babraham Institute)H-Index: 56
view all 12 authors...
Cited By4
Newest
#1Zhanye Zheng (TMUCIH: Tianjin Medical University Cancer Institute and Hospital)
#2Dandan Huang (TMUCIH: Tianjin Medical University Cancer Institute and Hospital)
Last.Hongcheng Yao (HKU: University of Hong Kong)H-Index: 1
view all 0 authors...
#1François Aguet (Broad Institute)H-Index: 19
#2Alvaro N. Barbeira (U of C: University of Chicago)H-Index: 5
Last.Silva Kasela (Columbia University)H-Index: 1
view all 0 authors...
#1Benjamin Walker (UNC: University of North Carolina at Chapel Hill)
#2Dane Taylor (SUNY: State University of New York System)H-Index: 11
Last.M. Gregory Forest (UNC: University of North Carolina at Chapel Hill)H-Index: 24
view all 7 authors...
#1Paolo Provero (UNITO: University of Turin)H-Index: 31
#2Elisa Mariella (UNITO: University of Turin)H-Index: 1
Last.Stefano Gilotto (UNITO: University of Turin)
view all 5 authors...
#1Douglas W Yao (Harvard University)
#2Luke O'Connor (Harvard University)H-Index: 3
Last.Alexander Gusev (Harvard University)H-Index: 21
view all 0 authors...
#1Ronald P.H. de Jongh (WUR: Wageningen University and Research Centre)
#2Aalt D. J. van Dijk (WUR: Wageningen University and Research Centre)H-Index: 27
Last.Dick de Ridder (WUR: Wageningen University and Research Centre)H-Index: 33
view all 0 authors...
#1Tayaza Fadason (University of Auckland)H-Index: 2
#2William Schierding (University of Auckland)H-Index: 7
Last.Justin M. O'Sullivan (University of Auckland)H-Index: 15
view all 6 authors...
View next paperHigher-order chromatin domains link eQTLs with the expression of far-away genes