Massively parallel in vivo CRISPR screening identifies RNF20/40 as epigenetic regulators of cardiomyocyte maturation

Nathan J. VanDusen, Julianna Y. Lee, Weiliang Gu, Catalina E. Butler, Isha Sethi, Yanjiang Zheng, Justin S. King, Pingzhu Zhou, Shengbao Suo, Yuxuan Guo, Qing Ma, Guo-Cheng Yuan and William T. Pu ()
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Nathan J. VanDusen: Boston Children’s Hospital
Julianna Y. Lee: Boston Children’s Hospital
Weiliang Gu: Boston Children’s Hospital
Catalina E. Butler: Boston Children’s Hospital
Isha Sethi: Boston Children’s Hospital
Yanjiang Zheng: Boston Children’s Hospital
Justin S. King: Boston Children’s Hospital
Pingzhu Zhou: Boston Children’s Hospital
Shengbao Suo: Dana-Farber Cancer Institute
Yuxuan Guo: Boston Children’s Hospital
Qing Ma: Boston Children’s Hospital
Guo-Cheng Yuan: Icahn School of Medicine at Mount Sinai
William T. Pu: Boston Children’s Hospital

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract The forward genetic screen is a powerful, unbiased method to gain insights into biological processes, yet this approach has infrequently been used in vivo in mammals because of high resource demands. Here, we use in vivo somatic Cas9 mutagenesis to perform an in vivo forward genetic screen in mice to identify regulators of cardiomyocyte (CM) maturation, the coordinated changes in phenotype and gene expression that occur in neonatal CMs. We discover and validate a number of transcriptional regulators of this process. Among these are RNF20 and RNF40, which form a complex that monoubiquitinates H2B on lysine 120. Mechanistic studies indicate that this epigenetic mark controls dynamic changes in gene expression required for CM maturation. These insights into CM maturation will inform efforts in cardiac regenerative medicine. More broadly, our approach will enable unbiased forward genetics across mammalian organ systems.

Date: 2021
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DOI: 10.1038/s41467-021-24743-z

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