Conserved Epigenetic Regulatory Logic Infers Genes Governing Cell Identity

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 Bodén; Nathan J Palpant

doi:10.1016/j.cels.2020.11.001

Conserved Epigenetic Regulatory Logic Infers Genes Governing Cell Identity

Cell Syst. 2020 Dec 16;11(6):625-639.e13. doi: 10.1016/j.cels.2020.11.001. Epub 2020 Dec 4.

Authors

Woo Jun Shim¹, Enakshi Sinniah², Jun Xu², Burcu Vitrinel³, Michael Alexanian⁴, Gaia Andreoletti⁵, Sophie Shen², Yuliangzi Sun², Brad Balderson¹, Carles Boix⁶, Guangdun Peng⁷, Naihe Jing⁷, Yuliang Wang⁸, Manolis Kellis⁶, Patrick P L Tam⁹, Aaron Smith¹⁰, Michael Piper¹¹, Lionel Christiaen³, Quan Nguyen², Mikael Bodén¹², Nathan J Palpant¹³

Affiliations

¹ School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
² Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
³ Center for Developmental Genetics, Department of Biology, New York University, New York, NY, USA.
⁴ Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA.
⁵ Institute for Computational Health Sciences, University of California, San Francisco, CA 94158, USA.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁷ CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences and Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China; State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
⁸ Paul G. Allen School of Computer Science and Engineering and Institute for Stem Cell & Regenerative Medicine, University of Washington, Seattle, WA, USA.
⁹ The University of Sydney, Children's Medical Research Institute, and School of Medical Sciences, Faculty of Medicine and Health, Westmead, NSW 2145, Australia.
¹⁰ Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia; Translational Research Institute, Woolloongabba, Brisbane, Australia.
¹¹ School of Biomedical Sciences, The University of Queensland, Brisbane, Australia; Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
¹² School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia. Electronic address: [email protected].
¹³ Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. Electronic address: [email protected].

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.

Keywords: EpiMap; H3K27me3; TRIAGE; cell differentiation; computational method; epigenetic; pluripotent stem cell; predictions; single cell RNA-seq.

Conserved Epigenetic Regulatory Logic Infers Genes Governing Cell Identity

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