Journal
CELL SYSTEMS
Volume 11, Issue 1, Pages 25-+Publisher
CELL PRESS
DOI: 10.1016/j.cels.2020.06.004
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Funding
- UK Research and Innovation (UKRI) [1645504]
- Darwin Trust fellowship
- Marie Sklodowska-Curie Individual Fellowship [751439]
- BBSRC Discovery fellowship [BB/T009713/1]
- BBSRC [BBS/E/B/000C0422]
- Wellcome Trust [105031/Z/14/Z, 210754/Z/18/Z]
- EMBL
- BMBF
- Volkswagen Foundation
- EU (ERC ) [DECODE 810296]
- Marie Curie Actions (MSCA) [751439] Funding Source: Marie Curie Actions (MSCA)
- Wellcome Trust [105031/Z/14/Z, 210754/Z/18/Z] Funding Source: Wellcome Trust
- BBSRC [BBS/E/B/000C0422, BBS/E/B/000C0426, BBS/E/B/000C0421, BB/T009713/1, 1645504] Funding Source: UKRI
- MRC [MR/M008975/1] Funding Source: UKRI
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Zygotic genome activation (ZGA) is an essential transcriptional event in embryonic development that coincides with extensive epigenetic reprogramming. Complex manipulation techniques and maternal stores of proteins preclude large-scale functional screens for ZGA regulators within early embryos. Here, we combined pooled CRISPR activation (CRISPRa) with single-cell transcriptomics to identify regulators of ZGA-like transcription in mouse embryonic stem cells, which serve as a tractable, in vitro proxy of early mouse embryos. Using multi-omics factor analysis (MOFA+) applied to similar to 200,000 single-cell transcriptomes comprising 230 CRISPRa perturbations, we characterized molecular signatures of ZGA and uncovered 24 factors that promote a ZGA-like response. Follow-up assays validated top screen hits, including the DNA-binding protein Dppa2, the chromatin remodeler Smarca5, and the transcription factor Patz1, and functional experiments revealed that Smarca5's regulation of ZGA-like transcription is dependent on Dppa2. Together, our single-cell transcriptomic profiling of CRISPRa-perturbed cells provides both system-level and molecular insights into the mechanisms that orchestrate ZGA.
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