Histone demethylase KDM5 regulates cardiomyocyte maturation by promoting fatty acid oxidation, oxidative phosphorylation, and myofibrillar organization

Manisha Deogharia; Leslye Venegas-Zamora; Akanksha Agrawal; Miusi Shi; Abhinav K Jain; Kevin J McHugh; Francisco Altamirano; Ali J Marian; Priyatansh Gurha

doi:10.1093/cvr/cvae014

journal article Jan 17, 2024

Histone demethylase KDM5 regulates cardiomyocyte maturation by promoting fatty acid oxidation, oxidative phosphorylation, and myofibrillar organization

Manisha Deogharia

Leslye Venegas-Zamora Akanksha Agrawal

Miusi Shi

Abhinav K Jain Kevin J McHugh Francisco Altamirano

Ali J Marian Priyatansh Gurha

Cardiovascular Research Vol. 120 No. 6 pp. 630-643 · Oxford University Press (OUP)

View at Publisher Save 10.1093/cvr/cvae014

Abstract

Abstract

Aims
Human pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) provide a platform to identify and characterize factors that regulate the maturation of CMs. The transition from an immature foetal to an adult CM state entails coordinated regulation of the expression of genes involved in myofibril formation and oxidative phosphorylation (OXPHOS) among others. Lysine demethylase 5 (KDM5) specifically demethylates H3K4me1/2/3 and has emerged as potential regulators of expression of genes involved in cardiac development and mitochondrial function. The purpose of this study is to determine the role of KDM5 in iPSC-CM maturation.

Methods and results
KDM5A, B, and C proteins were mainly expressed in the early post-natal stages, and their expressions were progressively downregulated in the post-natal CMs and were absent in adult hearts and CMs. In contrast, KDM5 proteins were persistently expressed in the iPSC-CMs up to 60 days after the induction of myogenic differentiation, consistent with the immaturity of these cells. Inhibition of KDM5 by KDM5-C70 -a pan-KDM5 inhibitor, induced differential expression of 2372 genes, including upregulation of genes involved in fatty acid oxidation (FAO), OXPHOS, and myogenesis in the iPSC-CMs. Likewise, genome-wide profiling of H3K4me3 binding sites by the cleavage under targets and release using nuclease assay showed enriched of the H3K4me3 peaks at the promoter regions of genes encoding FAO, OXPHOS, and sarcomere proteins. Consistent with the chromatin and gene expression data, KDM5 inhibition increased the expression of multiple sarcomere proteins and enhanced myofibrillar organization. Furthermore, inhibition of KDM5 increased H3K4me3 deposits at the promoter region of the ESRRA gene and increased its RNA and protein levels. Knockdown of ESRRA in KDM5-C70-treated iPSC-CM suppressed expression of a subset of the KDM5 targets. In conjunction with changes in gene expression, KDM5 inhibition increased oxygen consumption rate and contractility in iPSC-CMs.

Conclusion
KDM5 inhibition enhances maturation of iPSC-CMs by epigenetically upregulating the expressions of OXPHOS, FAO, and sarcomere genes and enhancing myofibril organization and mitochondrial function.

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Details

Published: Jan 17, 2024
Vol/Issue: 120(6)
Pages: 630-643
License: View

Authors

M

Manisha Deogharia

Center for Cardiovascular Genetics, Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston , 6770 Bertner Street, C950G, Houston, TX 77030 , USA

L

Leslye Venegas-Zamora

Department of Cardiovascular Sciences, Houston Methodist Research Institute , 6670 Bertner Avenue, Houston, Texas 77030 , USA

A

Akanksha Agrawal

Department of Cardiovascular Sciences, Houston Methodist Research Institute , 6670 Bertner Avenue, Houston, Texas 77030 , USA

M

Miusi Shi

Department of Bioengineering, Rice University , 6500 Main Street, Houston, TX 77030 , USA

A

Abhinav K Jain

Department of Epigenetics and Molecular Carcinogenesis, Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center , 1515 Holcombe Blvd, Houston, TX 77030 , USA

K

Kevin J McHugh

Department of Bioengineering, Rice University , 6500 Main Street, Houston, TX 77030 , USA; Department of Chemistry, Rice University , Houston, 6500 Main Street, Houston, TX 77030 , USA

F

Francisco Altamirano

Department of Cardiovascular Sciences, Houston Methodist Research Institute , 6670 Bertner Avenue, Houston, Texas 77030 , USA; Department of Cardiothoracic Surgery, Weill Cornell Medical College, Cornell University , Ithaca, NY , USA

A

Ali J Marian

Center for Cardiovascular Genetics, Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston , 6770 Bertner Street, C950G, Houston, TX 77030 , USA

P

Priyatansh Gurha

Center for Cardiovascular Genetics, Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston , 6770 Bertner Street, C950G, Houston, TX 77030 , USA

Cite This Article

Manisha Deogharia, Leslye Venegas-Zamora, Akanksha Agrawal, et al. (2024). Histone demethylase KDM5 regulates cardiomyocyte maturation by promoting fatty acid oxidation, oxidative phosphorylation, and myofibrillar organization. Cardiovascular Research, 120(6), 630-643. https://doi.org/10.1093/cvr/cvae014

Histone demethylase KDM5 regulates cardiomyocyte maturation by promoting fatty acid oxidation, oxidative phosphorylation, and myofibrillar organization

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