Journal
CELL
Volume 183, Issue 4, Pages 1103-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2020.09.056
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Funding
- Allen Distinguished Investigator Program through the Paul G. Allen Frontiers Group
- Chan Zuckerberg Initiative
- NIH New Innovator Award [DP2]
- NHGRI Center for Cell Circuits
- Klarman Cell Observatory
- BRAIN Initiative
- Smith Family Foundation Odyssey Award
- NIH [R01-AR070825]
- Charles A. King Trust postdoctoral research fellowship
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Cell differentiation and function are regulated across multiple layers of gene regulation, including modulation of gene expression by changes in chromatin accessibility. However, differentiation is an asynchronous process precluding a temporal understanding of regulatory events leading to cell fate commitment. Here we developed simultaneous high-throughput ATAC and RNA expression with sequencing (SHARE-seq), a highly scalable approach for measurement of chromatin accessibility and gene expression in the same single cell, applicable to different tissues. Using 34,774 joint profiles from mouse skin, we develop a computational strategy to identify cis-regulatory interactions and define domains of regulatory chromatin (DORCs) that significantly overlap with super-enhancers. During lineage commitment, chromatin accessibility at DORCs precedes gene expression, suggesting that changes in chromatin accessibility may prime cells for lineage commitment. We computationally infer chromatin potential as a quantitative measure of chromatin lineage-priming and use it to predict cell fate outcomes. SHARE-seq is an extensible platform to study regulatory circuitry across diverse cells in tissues.
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