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

Sakamoto, Tomoya; Batmanov, Kirill; Wan, Shibiao; Guo, Yuanjun; Lai, Ling; Vega, Rick B.; Kelly, Daniel P.

doi:10.1038/s41467-022-29733-3

Cited by 29 publications

(36 citation statements)

References 88 publications

(149 reference statements)

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“…To further test whether Esrrg expression is downregulated by LSD1, we made use of H9c2 rat cardiomyocytes, in which ERRγ is functionally involved in the differentiation ( Sakamoto et al, 2022 ). Inhibition of LSD1 in H9c2 cells led to significant upregulation of Esrrg and its downstream Perm1 ( Figure 5—figure supplement 1C ), whereas these genes were downregulated in LSD1-overexpressing H9c2 cells ( Figure 5—figure supplement 1D and E ).…”

Section: Resultsmentioning

confidence: 99%

LSD1 defines the fiber type-selective responsiveness to environmental stress in skeletal muscle

Araki

Hino

Anan

et al. 2023

eLife

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Skeletal muscle exhibits remarkable plasticity in response to environmental cues, with stress-dependent effects on the fast-twitch and slow-twitch fibers. Although stress-induced gene expression underlies environmental adaptation, it is unclear how transcriptional and epigenetic factors regulate fiber type-specific responses in the muscle. Here, we show that flavin-dependent lysine-specific demethylase-1 (LSD1) differentially controls responses to glucocorticoid and exercise in postnatal skeletal muscle. Using skeletal muscle-specific LSD1-knockout mice and in vitro approaches, we found that LSD1 loss exacerbated glucocorticoid-induced atrophy in the fast fiber-dominant muscles, with reduced nuclear retention of Foxk1, an anti-autophagic transcription factor. Furthermore, LSD1 depletion enhanced endurance exercise-induced hypertrophy in the slow fiber-dominant muscles, by induced expression of ERRγ, a transcription factor that promotes oxidative metabolism genes. Thus, LSD1 serves as an ‘epigenetic barrier’ that optimizes fiber type-specific responses and muscle mass under the stress conditions. Our results uncover that LSD1 modulators provide emerging therapeutic and preventive strategies against stress-induced myopathies such as sarcopenia, cachexia, and disuse atrophy.

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Section: Resultsmentioning

confidence: 99%

LSD1 defines the fiber type-selective responsiveness to environmental stress in skeletal muscle

Araki

Hino

Anan

et al. 2023

eLife

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“…S8F). ESRRG was known to regulate the expression of cardiac genes via interaction with GATA4 and GATA4-independent metabolic genes 45 . Moreover, we also observed that the motif for TEADs was enriched upon occupancy of GATA4 (Fig.…”

Section: Resultsmentioning

confidence: 99%

GATA4 regulates mitochondrial biogenesis and functions during cardiac development and rescues cardiac and mitochondrial functions impaired by TKIs

Liu

Duren

et al. 2022

Preprint

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Tyrosine kinase inhibitors (TKIs) have been widely used for cancer chemotherapy, but they also cause cardiotoxicities in cancer patients. In this study, we used human stem cells as an in-vitro system to interrogate the mechanisms underlying drug-induced toxicity in differentiated cardiomyocytes, including anticancer tyrosine kinase inhibitor (TKI) drugs, including imatinib, sunitinib, and vandetanib. Sublethal TKI exposure produces multiple effects, including disarranged sarcomere structure, interrupted Ca2+-handling, and impaired mitochondrial function, evident of TKI-induced toxicity in differentiated cardiomyocytes. GATA4-mediated regulatory networks, including key mitochondrial target genes, emerge as significant molecular signatures in integrated analyses of transcriptome and chromatin accessibility dynamics. We find that, on a molecular level, GATA4 acts as a regulatory factor in mitochondrial biogenesis and OXPHOS by directly regulating specific metabolism-related genes, such as PPARGC1A. Functional genomic experiments targeting GATA4 reveals that GATA4 upregulation by CRISPR-activation is able to restore mitochondrial morphology and OXPHOS upon TKI exposure. In addition, we also identified that GATA4 is involved in regulation of mitochondrial biogenesis during early cardiac differentiation; inhibition of GATA4 during differentiation reduces mitochondrial DNA content, ATP production, and OXPHOS in differentiated cardiomyocytes, demonstrating a developmental role of GATA4 in metabolic management during early cardiac differentiation. Altogether, our study identifies a novel link between GATA4 and mitochondria in cardiomyocytes, and identifies GATA4 as a promising therapeutic target for reducing TKI-induced cardiotoxicity for human health.

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“…However, the regulation of mitochondrial metabolism was shown to be independent from GATA-4 activity. Moreover, PGC-1α activity was recognized for its essential role in the transcriptional regulation by ERRγ ( 86 ).…”

Section: Signaling Pathways Potentially Associated With Human Induced...mentioning

confidence: 99%

Using human induced pluripotent stem cell-derived cardiomyocytes to understand the mechanisms driving cardiomyocyte maturation

Hamledari

Asghari

Jayousi

et al. 2022

Front. Cardiovasc. Med.

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Cardiovascular diseases are the leading cause of mortality and reduced quality of life globally. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a personalized platform to study inherited heart diseases, drug-induced cardiac toxicity, and cardiac regenerative therapy. However, the immaturity of CMs obtained by current strategies is a major hurdle in utilizing hiPSC-CMs at their fullest potential. Here, the major findings and limitations of current maturation methodologies to enhance the utility of hiPSC-CMs in the battle against a major source of morbidity and mortality are reviewed. The most recent knowledge of the potential signaling pathways involved in the transition of fetal to adult CMs are assimilated. In particular, we take a deeper look on role of nutrient sensing signaling pathways and the potential role of cap-independent translation mediated by the modulation of mTOR pathway in the regulation of cardiac gap junctions and other yet to be identified aspects of CM maturation. Moreover, a relatively unexplored perspective on how our knowledge on the effects of preterm birth on cardiovascular development can be actually utilized to enhance the current understanding of CM maturation is examined. Furthermore, the interaction between the evolving neonatal human heart and brown adipose tissue as the major source of neonatal thermogenesis and its endocrine function on CM development is another discussed topic which is worthy of future investigation. Finally, the current knowledge regarding transcriptional mediators of CM maturation is still limited. The recent studies have produced the groundwork to better understand CM maturation in terms of providing some of the key factors involved in maturation and development of metrics for assessment of maturation which proves essential for future studies on in vitro PSC-CMs maturation.

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

Cited by 29 publications

References 88 publications

LSD1 defines the fiber type-selective responsiveness to environmental stress in skeletal muscle

LSD1 defines the fiber type-selective responsiveness to environmental stress in skeletal muscle

GATA4 regulates mitochondrial biogenesis and functions during cardiac development and rescues cardiac and mitochondrial functions impaired by TKIs

Using human induced pluripotent stem cell-derived cardiomyocytes to understand the mechanisms driving cardiomyocyte maturation

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