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

VanDusen, Nathan J.; Lee, Julianna Y.; Gu, Weiliang; Butler, Catalina E.; Sethi, Isha; Zheng, Yanjiang; King, Justin S.; Zhou, Pingzhu; Suo, Shengbao; Guo, Yuxuan; Ma, Qing; Yuan, Guo‐Cheng; Pu, William William

doi:10.1038/s41467-021-24743-z

Cited by 34 publications

(31 citation statements)

References 72 publications

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“…The functions and gene targets of GATA6 are partially redundant with GATA4 35 – 37 . To determine whether ERRγ and GATA6 also shared targets, we conducted an intersection analysis with GATA6 ChIP-seq in hiPSC-CMs 18 and our ERRγ ChIP-seq datasets.…”

Section: Resultsmentioning

confidence: 99%

The nuclear receptor ERR cooperates with the cardiogenic factor GATA4 to orchestrate cardiomyocyte maturation

et al. 2022

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Estrogen-related receptors (ERR) α and γ were shown recently to serve as regulators of cardiac maturation, yet the underlying mechanisms have not been delineated. Herein, we find that ERR signaling is necessary for induction of genes involved in mitochondrial and cardiac-specific contractile processes during human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) differentiation. Genomic interrogation studies demonstrate that ERRγ occupies many cardiomyocyte enhancers/super-enhancers, often co-localizing with the cardiogenic factor GATA4. ERRγ interacts with GATA4 to cooperatively activate transcription of targets involved in cardiomyocyte-specific processes such as contractile function, whereas ERRγ-mediated control of metabolic genes occurs independent of GATA4. Both mechanisms require the transcriptional coregulator PGC-1α. A disease-causing GATA4 mutation is shown to diminish PGC-1α/ERR/GATA4 cooperativity and expression of ERR target genes are downregulated in human heart failure samples suggesting that dysregulation of this circuitry may contribute to congenital and acquired forms of heart failure.

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Section: Resultsmentioning

confidence: 99%

The nuclear receptor ERR cooperates with the cardiogenic factor GATA4 to orchestrate cardiomyocyte maturation

et al. 2022

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“…Furthermore, extensive studies have been conducted on the mechanisms by which H3K4 and H3K27 methylations impact heart development 11,14,15 . More recently, a critical role for histone H2B ubiquitylation (H2Bub) was demonstrated in cardiac development 16,17 . Knockdown of the Xenopus H2Bub E3 ligases, rnf20 (Ring finger protein 20) and rnf40 (Ring finger protein 40) 18 , beginning at the two-cell stage, influences cardiac looping and left-right (LR) asymmetry during early embryonic development 16 .…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, the results of an in vivo CRISPR/Cas9 genetic screen suggested that RNF20/40 is involved in cardiomyocyte (CM) maturation via H2Bub deposition 17 . Thus, RNF20 appears to be relevant to both CHD and CM maturation 16,19 . Nevertheless, the molecular function of RNF20 during temporal development of mammalian heart remains uncharacterized.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, the results of an in vivo CRISPR/Cas9 genetic screen suggested that RNF20/40 is involved in cardiomyocyte (CM) maturation via H2Bub deposition 18 . Thus, RNF20 appears to be relevant to both CHD and CM maturation 17,20 . The addition of a single ubiquitin on H2B disrupts local and higher-order structures of compacted chromatin 21,22 .…”

Section: Introductionmentioning

confidence: 99%

“…Knockdown of the Xenopus H2Bub E3 ligases, rnf20 (Ring finger protein 20) and rnf40 (Ring finger protein 40) 19 , beginning at the two-cell stage, influences cardiac looping and left-right (LR) asymmetry during early embryonic development 17 . Furthermore, the results of an in vivo CRISPR/Cas9 genetic screen suggested that RNF20/40 is involved in cardiomyocyte (CM) maturation via H2Bub deposition 18 . Thus, RNF20 appears to be relevant to both CHD and CM maturation 17,20 .…”

Section: Introductionmentioning

confidence: 99%

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Chromatin state transition underlies the temporal changes in gene expression during cardiomyocyte maturation

Lin

Chang

Tseng

et al. 2021

Preprint

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Congenital heart disease (CHD) is often rooted in aberrant gene expression during heart development. As cells commit to a specific lineage during development, chromatin dynamics and developmental plasticity generally become more limited. However, it remains unclear how differentiated cardiomyocytes (CMs) undergo morphological and functional adaptations to the postnatal environment during the process of CM maturation. We sought to investigate the regulatory mechanisms that control postnatal cardiac gene networks. A time-series transcriptomic analysis of postnatal hearts revealed an integrated, time-ordered transcriptional network that regulates CM maturation. Remarkably, depletion of histone H2B ubiquitin ligase RNF20 after formation of the four-chamber heart disrupted these highly coordinated gene networks. As such, its ablation caused early-onset cardiomyopathy, a phenotype reminiscent of CHD. Furthermore, the dynamic modulation of chromatin accessibility by RNF20 during CM maturation was necessary for the operative binding of cardiac transcription factors that drive transcriptional gene networks. Together, our results reveal how epigenetic-mediated chromatin state transitions modulate time-ordered gene expression for CM maturation.

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Cardiomyocyte maturation and its reversal during cardiac regeneration

Beisaw

2022

Developmental Dynamics

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Cardiovascular disease is a leading cause of death worldwide. Due to the limited proliferative and regenerative capacity of adult cardiomyocytes, the lost myocardium is not replenished efficiently and is replaced by a fibrotic scar, which eventually leads to heart failure. Current therapies to cure or delay the progression of heart failure are limited; hence, there is a pressing need for regenerative approaches to support the failing heart. Cardiomyocytes undergo a series of transcriptional, structural, and metabolic changes after birth (collectively termed maturation), which is critical for their contractile function but limits the regenerative capacity of the heart. In regenerative organisms, cardiomyocytes revert from their terminally differentiated state into a less mature state (ie, dedifferentiation) to allow for proliferation and regeneration to occur. Importantly, stimulating adult cardiomyocyte dedifferentiation has been shown to promote morphological and functional improvement after myocardial infarction, further highlighting the importance of cardiomyocyte dedifferentiation in heart regeneration. Here, we review several hallmarks of cardiomyocyte maturation, and summarize how their reversal facilitates cardiomyocyte proliferation and heart regeneration. A detailed understanding of how cardiomyocyte dedifferentiation is regulated will provide insights into therapeutic options to promote cardiomyocyte de‐maturation and proliferation, and ultimately heart regeneration in mammals.

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

Cited by 34 publications

References 72 publications

The nuclear receptor ERR cooperates with the cardiogenic factor GATA4 to orchestrate cardiomyocyte maturation

The nuclear receptor ERR cooperates with the cardiogenic factor GATA4 to orchestrate cardiomyocyte maturation

Chromatin state transition underlies the temporal changes in gene expression during cardiomyocyte maturation

Cardiomyocyte maturation and its reversal during cardiac regeneration

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