Medical College of Wisconsin
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A transcriptional enhancer regulates cardiac maturation. Nat Cardiovasc Res 2024 Jun;3(6):666-684

Date

08/28/2024

Pubmed ID

39196225

Pubmed Central ID

PMC12306338

DOI

10.1038/s44161-024-00484-2

Scopus ID

2-s2.0-85194721283 (requires institutional sign-in at Scopus site)   6 Citations

Abstract

Cardiomyocyte maturation is crucial for generating adult cardiomyocytes and the application of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). However, regulation at the cis-regulatory element level and its role in heart disease remain unclear. Alpha-actinin 2 (ACTN2) levels increase during CM maturation. In this study, we investigated a clinically relevant, conserved ACTN2 enhancer's effects on CM maturation using hPSC and mouse models. Heterozygous ACTN2 enhancer deletion led to abnormal CM morphology, reduced function and mitochondrial respiration. Transcriptomic analyses in vitro and in vivo showed disrupted CM maturation and upregulated anabolic mammalian target for rapamycin (mTOR) signaling, promoting senescence and hindering maturation. As confirmation, ACTN2 enhancer deletion induced heat shock protein 90A expression, a chaperone mediating mTOR activation. Conversely, targeting the ACTN2 enhancer via enhancer CRISPR activation (enCRISPRa) promoted hPSC-CM maturation. Our studies reveal the transcriptional enhancer's role in cardiac maturation and disease, offering insights into potentially fine-tuning gene expression to modulate cardiomyocyte physiology.

Author List

Htet M, Lei S, Bajpayi S, Gangrade H, Arvanitis M, Zoitou A, Murphy S, Chen EZ, Koleini N, Lin BL, Kwon C, Tampakakis E

Author

Brian L. Lin PhD Assistant Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Actinin
Animals
Cell Differentiation
Cell Line
Enhancer Elements, Genetic
Gene Expression Regulation, Developmental
HSP90 Heat-Shock Proteins
Humans
Mice
Myocytes, Cardiac
Phenotype
Signal Transduction
TOR Serine-Threonine Kinases
Transcription, Genetic