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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Genetic variants associated with differential binding of PU.1 underpin GWAS variants associated with blood cell count and autoimmune diseases.
“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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Self-citationThe three-dimensional genome: principles and roles of long-distance interactions
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“Similar enrichments have been reported for QTLs affecting mRNA splicing (Fraser and Xie 2009, Li et al 2016), transcription factor binding (Waszak et al. 2015, Tehranchi et al. 2016), and chromatin accessibility (Kumasaka et al. 2016, Gate et al. 2018).”
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BackgroundMethodGRaNIE and GRaNPA: inference and evaluation of enhancer‐mediated gene regulatory networks
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“…as the activity by contact model (Nasser et al , 2021), purely based on genetics, such as eQTLs (Vo˜sa et al , 2021) or variable chromatin domains (Waszak et al , 2015), eGRNs by GRaNIE capture TF-peak-gene links based on variation due to genetic, epigenetic, or TF-activity differences across…”
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Strengthening Causal Inference for Complex Disease Using Molecular Quantitative Trait Loci
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“Non-coding variants, both in cis and trans , can exert strong in fl uence on DNAm, alter chromatin topology, and modulate the expression of target genes 15 – 18 .”
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“…indicated the presence of chromatin domains with associated signals between SNPs (Waszak et al. 2015; Grubert et al. 2015), but across the genome, Waszak et al. (2015) detected 14,559 domains, of which only 25 % were larger than 70 kb. Correlation of allelic bias in adjacent SNPs was also found…”
BackgroundNature and nurture of tissue-specific macrophage phenotypes
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Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4
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“Published by Elsevier G different chromosomes thanks to higher-order modular organization of gene regulation [18].”
BackgroundInterpretation of allele-specific chromatin accessibility using cell state–aware deep learning
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“far showed that the majority of the variants associated with allele-specific enhancer activity cannot be explained by TF motif alterations (Degner et al. 2012; Kilpinen et al. 2013; Maurano et al. 2015; Waszak et al. 2015; Deplancke et al. 2016; Kumasaka et al. 2016; Tehranchi et al. 2019).”
BackgroundNon-Random Genome Editing and Natural Cellular Engineering in Cognition-Based Evolution
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“Chromatin is an important regulator of gene expression [125] that links to the molecular determinants of cellular responses to stress and complex phenotypes in all organisms including humans [126].”
BackgroundTranscription factor regulation of eQTL activity across individuals and tissues
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“One thing made clear by functional annotation data is that both eQTLs and chromatin-QTLs are enriched in known TF binding sites [2,4,28].”
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“Although the term epigenetics means ‘above the genetics’, genetic variation has also been shown to play a substantial role in the degree of epigenetic variation across individuals 16–22 .”
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Principles and methods of in-silico prioritization of non-coding regulatory variants
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Chromatin Biology Impacts Adaptive Evolution of Filamentous Plant Pathogens
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Evaluating the impact of single nucleotide variants on transcription factor binding
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“However, the accumulated effect of multiple SNVs proximal or distal to a TFBS could alter local TF binding according to the TF–TF interaction and chromatin interaction models (58,59).”
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“5 HOMER motif score (1) JunB(bZIP, n = 237) (2) Fra1(bZIP, n = 268) (3) Fosl2(bZIP, n = 221) (4) Atf3(bZIP, n = 271) (5) BATF(bZIP, n = 262) (6) AP-1(bZIP, n = 253) (7) Fos(bZIP, n = 249) (8) Fra2(bZIP, n = 242) (9) Jun-AP1(bZIP, n = 197) (10) NF1(CTF, n = 127) (11) MafK(bZIP, n = 51) (12) CREB5(bZIP, n = 40) (13) FOX…”
Epigenomic charting and functional annotation of risk loci in renal cell carcinoma
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“We anticipate more large-scale QTL studies focusing on other molecular phenotypes, such as DNA methylation and histone modification, could be available in a wide range of tissues/cell types [27, 52 – 54].”
BackgroundChromatin modules and their implication in genomic organization and gene regulation
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Self-citationTime-dependent genetic effects on gene expression implicate aging processesPreprint
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“Two potential explanations could explain this phenomenon: rs76194250 might be a proxy of two independent variants, bound by different factors, and the expression of these factors could change over time (Wen et al. 2015).”
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“Even with this recognition, GWASs often fail to provide insight into the TFs, as well as the cell types, most affected.”
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Proteome-wide Systems Genetics to Identify Functional Regulators of Complex Traits
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Transcriptional Enhancers: Bridging the Genome and PhenomePreprint
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“Studies using 3C-based molecular analysis of the 3D genome organization have shown that chromosomes consist of relatively stable chromatin domains, referred to as topologically associating domains (TADs) (Fig.”
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- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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