Conserved Epigenetic Regulatory Logic Infers Genes Governing Cell Identity

Overview

Journal Cell Syst

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2020 Dec 5

PMID 33278344

Citations 16

Authors

Woo Jun Shim

Enakshi Sinniah

Jun Xu

Burcu Vitrinel

Michael Alexanian

Gaia Andreoletti

Sophie Shen

Yuliangzi Sun

Brad Balderson

Carles Boix

Guangdun Peng

Naihe Jing

Yuliang Wang

Manolis Kellis

Patrick P L Tam

Aaron Smith

Michael Piper

Lionel Christiaen

Quan Nguyen

Mikael Boden

Nathan J Palpant

Affiliations

Soon will be listed here.

Abstract

Determining genes that orchestrate cell differentiation in development and disease remains a fundamental goal of cell biology. This study establishes a genome-wide metric based on the gene-repressive trimethylation of histone H3 at lysine 27 (H3K27me3) across hundreds of diverse cell types to identify genetic regulators of cell differentiation. We introduce a computational method, TRIAGE, which uses discordance between gene-repressive tendency and expression to identify genetic drivers of cell identity. We apply TRIAGE to millions of genome-wide single-cell transcriptomes, diverse omics platforms, and eukaryotic cells and tissue types. Using a wide range of data, we validate the performance of TRIAGE in identifying cell-type-specific regulatory factors across diverse species including human, mouse, boar, bird, fish, and tunicate. Using CRISPR gene editing, we use TRIAGE to experimentally validate RNF220 as a regulator of Ciona cardiopharyngeal development and SIX3 as required for differentiation of endoderm in human pluripotent stem cells. A record of this paper's transparent peer review process is included in the Supplemental Information.

Citing Articles

Atlas of multilineage stem cell differentiation reveals TMEM88 as a developmental regulator of blood pressure.

Shen S, Werner T, Lukowski S, Andersen S, Sun Y, Shim W Nat Commun. 2025; 16(1):1356.

PMID: 39904980 PMC: 11794859. DOI: 10.1038/s41467-025-56533-2.

TRIAGE: an R package for regulatory gene analysis.

Zhao Q, Shim W, Sun Y, Sinniah E, Shen S, Boden M Brief Bioinform. 2025; 26(1.

PMID: 39800877 PMC: 11725390. DOI: 10.1093/bib/bbaf004.

Epigenetic regulation of complement C1Q gene expression.

Pegoraro S, Balduit A, Mangogna A, Kishore U, Ricci G, Agostinis C Front Immunol. 2024; 15:1498097.

PMID: 39697348 PMC: 11653359. DOI: 10.3389/fimmu.2024.1498097.

Cooperative insulation of regulatory domains by CTCF-dependent physical insulation and promoter competition.

Ealo T, Sanchez-Gaya V, Respuela P, Munoz-San Martin M, Martin-Batista E, Haro E Nat Commun. 2024; 15(1):7258.

PMID: 39179577 PMC: 11344162. DOI: 10.1038/s41467-024-51602-4.

TGF-β modulates cell fate in human ES cell-derived foregut endoderm by inhibiting Wnt and BMP signaling.

Funa N, Mjoseng H, de Lichtenberg K, Raineri S, Esen D, Egeskov-Madsen A Stem Cell Reports. 2024; 19(7):973-992.

PMID: 38942030 PMC: 11252478. DOI: 10.1016/j.stemcr.2024.05.010.

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