Conserved facultative heterochromatin across cell types identify regulatory sequences underpinning cell identity and disease
Date
2025
Authors
Sinniah, E.
Mizikovsky, D.
Shim, W.J.
Yeung Chow, C.S.
Souilmi, Y.
Cheng, F.-F.
Zeng, Z.
Laurie, J.
Foster, M.
Shah, S.
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Advisors
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Journal article
Citation
Nucleic Acids Research (NAR), 2025; 53(20):gkaf971-1-gkaf971-23
Statement of Responsibility
Enakshi Sinniah, Dalia Mizikovsky, Woo Jun Shim, Chris Siu Yeung Chow, Yassine Souilmi, Fei-Fei Cheng, Zhili Zeng, Jordan Laurie, Matthew Foster, Sonia Shah, Mikael Bodén, Jian Zeng, Bastien Llamas, Nathan J Palpant
Conference Name
Abstract
Cellular diversity is a product of evolution acting to establish divergent gene regulatory programs from a common genome. Here, we use cross-cell-type epigenetic conservation to gain insight into the impact of selective constraints on genome function and phenotypic variation. By comparing chromatin accessibility across hundreds of diverse cell-types, we identify 1.4% of the human genome safeguarded by conserved domains of facultative heterochromatin, which we term regions under “cellular constraint”. We calculate single-base resolution cellular constraint scores and demonstrate robust prediction of functionally important coding and noncoding loci in a cell-type-, trait-, and disease-agnostic manner. Cellular constraint annotation enhances causal variant identification, drug discovery, and clinical diagnostic predictions. Furthermore, cell-constrained sequences share signals of positive and negative selection, suggesting a dynamic role in influencing human traits and cellular phenotypes. Overall, this study demonstrates that evolutionary chromatin dynamics can be leveraged to inform the translation of genetic discoveries into effective biological, therapeutic, and clinical outcomes.
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© The Author(s) 2025. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.