Comparative analysis of diverse cell states establishes an epigenetic basis for inferring regulatory genes governing cell identity

Shim, W. J.; Sinniah, E.; Xu, J.; Vitrinel, B.; Alexenian, M.; Andreoletti, G.; Shen, S.; Balderson, B.; Peng, G.; Jing, N.; Sun, Y.; Chhabra, Y.; Wang, Y.; Tam, P.; Smith, A.; Piper, M.; Srivastava, D.; Christiaen, L.; Nguyen, Q.; Boden, M.; Palpant, N.

doi:10.1101/635516

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bioRxiv · 10.1101/635516

Comparative analysis of diverse cell states establishes an epigenetic basis for inferring regulatory genes governing cell identity

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Abstract

Determining genes orchestrating 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 tri-methylation of histone 3 lysine 27 (H3K27me3) across hundreds of diverse cell types to identify genetic regulators of cell differentiation. We introduce a computational method, TRIAGE, that 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 TRIAGEs performance for 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 papers Transparent Peer Review process is included in the Supplemental Information.

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Shim, W. J., Sinniah, E., Xu, J., Vitrinel, B., Alexenian, M., Andreoletti, G., Shen, S., Balderson, B., Peng, G., Jing, N., Sun, Y., Chhabra, Y., Wang, Y., Tam, P., Smith, A., Piper, M., Srivastava, D., Christiaen, L., Nguyen, Q., Boden, M., Palpant, N.. 2019-05-12. Comparative analysis of diverse cell states establishes an epigenetic basis for inferring regulatory genes governing cell identity. https://doi.org/10.1101/635516

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