Journal
PROTEIN & CELL
Volume 11, Issue 9, Pages 661-679Publisher
OXFORD UNIV PRESS
DOI: 10.1007/s13238-020-00713-x
Keywords
circadian geneBMAL1; human embryonic stem cells; cell differentiation; cardiomyocytes; dilated cardiomyopathy; mitochondria
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Funding
- National Natural Science Foundation of China (NSFC) [81322003, 31571527, 31501098, 81500241, 81870600, 81570771, 31871189]
- Science and Technology Commission of Shanghai Municipality [17XD1400300, 17JC1400200]
- National Key R&D Program of China [2018YFC2000202]
- Haiju program of National Children's Medical Center [EK1125180102]
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Dysregulation of circadian rhythms associates with cardiovascular disorders. It is known that deletion of the core circadian geneBmal1in mice causes dilated cardiomyopathy. However, the biological rhythm regulation system in mouse is very different from that of humans. WhetherBMAL1plays a role in regulating human heart function remains unclear. Here we generated aBMAL1knockout human embryonic stem cell (hESC) model and further derived humanBMAL1deficient cardiomyocytes. We show thatBMAL1deficient hESC-derived cardiomyocytes exhibited typical phenotypes of dilated cardiomyopathy including attenuated contractility, calcium dysregulation, and disorganized myofilaments. In addition, mitochondrial fission and mitophagy were suppressed inBMAL1deficient hESC-cardiomyocytes, which resulted in significantly attenuated mitochondrial oxidative phosphorylation and compromised cardiomyocyte function. We also found that BMAL1 binds to the E-box element in the promoter region ofBNIP3gene and specifically controls BNIP3 protein expression.BMAL1knockout directly reduced BNIP3 protein level, causing compromised mitophagy and mitochondria dysfunction and thereby leading to compromised cardiomyocyte function. Our data indicated that the core circadian geneBMAL1is critical for normal mitochondria activities and cardiac function. Circadian rhythm disruption may directly link to compromised heart function and dilated cardiomyopathy in humans.
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