Journal
CELL SYSTEMS
Volume 11, Issue 6, Pages 625-+Publisher
CELL PRESS
DOI: 10.1016/j.cels.2020.11.001
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Funding
- Children's Hospital Foundation Queensland [50268]
- American Heart Association [18PRE33990254]
- NIH/NHLBI [R01 HL108643]
- Swiss National Science Foundation [P2LAP3_178056]
- National Health and Medical Research Council of Australia [1110751, 1143163]
- ARC DECRA [ARC DECRA DE190100116]
- Australian Research Council [SR1101002]
- Swiss National Science Foundation (SNF) [P2LAP3_178056] Funding Source: Swiss National Science Foundation (SNF)
- National Health and Medical Research Council of Australia [1143163] Funding Source: NHMRC
- Australian Research Council [SR1101002] Funding Source: Australian Research Council
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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.
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