A genome-wide CRISPR screen identifies BRD4 as a regulator of cardiomyocyte differentiation.

Autor: Padmanabhan A; Gladstone Institutes, San Francisco, CA, USA. arun.padmanabhan@gladstone.ucsf.edu.; Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA, USA. arun.padmanabhan@gladstone.ucsf.edu.; Chan Zuckerberg Biohub, San Francisco, CA, USA. arun.padmanabhan@gladstone.ucsf.edu., de Soysa TY; Gladstone Institutes, San Francisco, CA, USA., Pelonero A; Gladstone Institutes, San Francisco, CA, USA., Sapp V; Department of Medicine, University of California, San Diego, School of Medicine, San Diego, CA, USA.; Department of Pharmacology, University of California, San Diego, San Diego, CA, USA., Shah PP; Cardiovascular Institute, Epigenetics Institute, and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA., Wang Q; Cardiovascular Institute, Epigenetics Institute, and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA., Li L; Cardiovascular Institute, Epigenetics Institute, and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA., Lee CY; Gladstone Institutes, San Francisco, CA, USA.; Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA, USA., Sadagopan N; Gladstone Institutes, San Francisco, CA, USA.; Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA, USA., Nishino T; Gladstone Institutes, San Francisco, CA, USA., Ye L; Gladstone Institutes, San Francisco, CA, USA., Yang R; Cardiovascular Institute, Epigenetics Institute, and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA., Karnay A; Cardiovascular Institute, Epigenetics Institute, and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA., Poleshko A; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA., Bolar N; Cardiovascular Institute, Epigenetics Institute, and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA., Linares-Saldana R; Cardiovascular Institute, Epigenetics Institute, and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA., Ranade SS; Gladstone Institutes, San Francisco, CA, USA., Alexanian M; Gladstone Institutes, San Francisco, CA, USA.; Department of Pediatrics, University of California, San Francisco, School of Medicine, San Francisco, CA, USA., Morton SU; Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA.; Department of Pediatrics, Harvard Medical School, Boston, MA, USA., Jain M; Department of Medicine, University of California, San Diego, School of Medicine, San Diego, CA, USA.; Department of Pharmacology, University of California, San Diego, San Diego, CA, USA., Haldar SM; Gladstone Institutes, San Francisco, CA, USA.; Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA, USA.; Amgen Research, Cardiometabolic Disorders, South San Francisco, CA, USA., Srivastava D; Gladstone Institutes, San Francisco, CA, USA. deepak.srivastava@gladstone.ucsf.edu.; Department of Pediatrics, University of California, San Francisco, School of Medicine, San Francisco, CA, USA. deepak.srivastava@gladstone.ucsf.edu.; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes, San Francisco, CA, USA. deepak.srivastava@gladstone.ucsf.edu.; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA. deepak.srivastava@gladstone.ucsf.edu., Jain R; Cardiovascular Institute, Epigenetics Institute, and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. jainr@pennmedicine.upenn.edu.; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA. jainr@pennmedicine.upenn.edu.
Jazyk: angličtina
Zdroj: Nature cardiovascular research [Nat Cardiovasc Res] 2024 Mar; Vol. 3 (3), pp. 317-331. Date of Electronic Publication: 2024 Feb 23.
DOI: 10.1038/s44161-024-00431-1
Abstrakt: Human induced pluripotent stem cell (hiPSC) to cardiomyocyte (CM) differentiation has reshaped approaches to studying cardiac development and disease. In this study, we employed a genome-wide CRISPR screen in a hiPSC to CM differentiation system and reveal here that BRD4, a member of the bromodomain and extraterminal (BET) family, regulates CM differentiation. Chemical inhibition of BET proteins in mouse embryonic stem cell (mESC)-derived or hiPSC-derived cardiac progenitor cells (CPCs) results in decreased CM differentiation and persistence of cells expressing progenitor markers. In vivo, BRD4 deletion in second heart field (SHF) CPCs results in embryonic or early postnatal lethality, with mutants demonstrating myocardial hypoplasia and an increase in CPCs. Single-cell transcriptomics identified a subpopulation of SHF CPCs that is sensitive to BRD4 loss and associated with attenuated CM lineage-specific gene programs. These results highlight a previously unrecognized role for BRD4 in CM fate determination during development and a heterogenous requirement for BRD4 among SHF CPCs.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
Externí odkaz: