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Population Variation and Genetic Control of Modular Chromatin Architecture in Humans
Open accessAbstract
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.
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“For example, genetic variants associated with differential binding of PU.1 were found to underpin GWAS variants associated with blood cell count and autoimmune diseases [213–215].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [213]
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“…levels (Montgomery et al , 2010; Pickrell et al , 2010), DNA methylation (Gibbs et al , 2010; Bell et al , 2011), histone marks (Grubert et al , 2015; Waszak et al , 2015) and proteome variation (Vincent et al , 2010; Albert et al , 2014; Parts et al , 2014; Battle et al , 2015) (Fig 2A).”
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Metadata
- Authors
- Waszak, S. M., Delaneau, O., Gschwind, A. R., Kilpinen, H., Raghav, S. K., Witwicki, R. M., Orioli, A., Wiederkehr, M., Panousis, N. I., Yurovsky, A., Romano-Palumbo, L., Planchon, A., Bielser, D., Padioleau, I., Udin, G., Thurnheer, S., Hacker, D., Hernandez, N., Reymond, A., Deplancke, B., & Dermitzakis, E. T.
- Affiliations
- SIB Swiss Institute of Bioinformatics (CH)
- University of Geneva (CH)
- École Polytechnique Fédérale de Lausanne (CH)
- University of Lausanne (CH)
- Corresponding author
- Deplancke, Bart
- Dermitzakis, Emmanouil T.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 162
- Issue
- 5
- Pages
- 1039-1050
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W1796801877
- Cited by
- 214
- References
- 49
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 17 · 2023: 16 · 2022: 17 · 2021: 19 · 2020: 12 · 2019: 23 · 2018: 24 · 2017: 30 · 2016: 34 · 2015: 6
- FWCI
- 13.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- Swiss National Science Foundation (CRSI33_130326, 31003A_132958, 31003A_130342, 149984, 31003A_129835, 31003A_138323)
- European Research Council
- Louis-Jeantet Foundation
- SystemsX (3826)
- NIH (MH101814)
- European Molecular Biology Organization (ALTF 2010-337)
- doctoral school of the Faculty of Biology and Medicine
- University of Lausanne
- NCCR Frontiers in Genetics Program
- Japan Science and Technology Agency
- ETH Zürich
- École Polytechnique Fédérale de Lausanne
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- cis-regulatory elements, histone modifications, PU.1, RNA polymerase II, gene expression, transcription factor binding, lymphoblastoid cell lines, individual genetic variation, chromatin structure
- MeSH terms
- Chromatin, Chromosomes, Human, Gene Expression Regulation, Genetics, Population, Humans, Regulatory Sequences, Nucleic Acid, Transcription Factors, Genetic Variation, Genome, Human, Quantitative Trait Loci
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