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

Tomoya Sakamoto, Kirill Batmanov, Shibiao Wan, Yuanjun Guo, Ling Lai, Rick B. Vega and Daniel P. Kelly ()
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Tomoya Sakamoto: Perelman School of Medicine at the University of Pennsylvania
Kirill Batmanov: Perelman School of Medicine at the University of Pennsylvania
Shibiao Wan: Perelman School of Medicine at the University of Pennsylvania
Yuanjun Guo: Perelman School of Medicine at the University of Pennsylvania
Ling Lai: Perelman School of Medicine at the University of Pennsylvania
Rick B. Vega: Sanford Burnham Prebys Medical Discovery Institute
Daniel P. Kelly: Perelman School of Medicine at the University of Pennsylvania

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-29733-3

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