한빛사논문
- 조회500
Kyu-Won Cho 1, Mark Andrade 1, Seongho Bae 1, Sangsung Kim 1, Jin Eyun Kim 1, Er Yearn Jang 1, Sangho Lee 1, Ahsan Husain 1, Roy L Sutliff 2, John W Calvert 3, Changwon Park 4, Young-Sup Yoon 1,5
1Division of Cardiology, Emory University School of Medicine, Atlanta, GA. (K.-W.C., M.A., S.B., S.K., J.E.K., E.Y.J., S.L., A.H., Y.-s.Y.).
2Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University School of Medicine, Atlanta, GA. (R.L.S.).
3Department of Medicine, Division of Cardiothoracic Surgery, Department of Surgery, Carlyle Fraser Heart Center, Emory University School of Medicine, Atlanta, GA. (J.W.C.).
4Department of Molecular and Cellular Physiology, Louisiana State University Health Science Center, Shreveport (C.P.).
5Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea (Y.-s.Y.).
Correspondence to: Young-sup Yoon, MD, PhD
Abstract
BACKGROUND:
Shortly after birth, cardiomyocytes exit the cell cycle and cease proliferation. At present, the regulatory mechanisms for this loss of proliferative capacity are poorly understood. CBX7 (chromobox 7), a polycomb group (PcG) protein, regulates the cell cycle, but its role in cardiomyocyte proliferation is unknown.
METHODS:
We profiled CBX7 expression in the mouse hearts through quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry. We overexpressed CBX7 in neonatal mouse cardiomyocytes through adenoviral transduction. We knocked down CBX7 by using constitutive and inducible conditional knockout mice (Tnnt2-Cre;Cbx7fl/+ and Myh6-MCM;Cbx7fl/fl, respectively). We measured cardiomyocyte proliferation by immunostaining of proliferation markers such as Ki67, phospho-histone 3, and cyclin B1. To examine the role of CBX7 in cardiac regeneration, we used neonatal cardiac apical resection and adult myocardial infarction models. We examined the mechanism of CBX7-mediated repression of cardiomyocyte proliferation through coimmunoprecipitation, mass spectrometry, and other molecular techniques.
RESULT:
We explored Cbx7 expression in the heart and found that mRNA expression abruptly increased after birth and was sustained throughout adulthood. Overexpression of CBX7 through adenoviral transduction reduced proliferation of neonatal cardiomyocytes and promoted their multinucleation. On the other hand, genetic inactivation of Cbx7 increased proliferation of cardiomyocytes and impeded cardiac maturation during postnatal heart growth. Genetic ablation of Cbx7 promoted regeneration of neonatal and adult injured hearts. Mechanistically, CBX7 interacted with TARDBP (TAR DNA-binding protein 43) and positively regulated its downstream target, RBM38 (RNA Binding Motif Protein 38), in a TARDBP-dependent manner. Overexpression of RBM38 inhibited the proliferation of CBX7-depleted neonatal cardiomyocytes.
CONCLUSIONS:
Our results demonstrate that CBX7 directs the cell cycle exit of cardiomyocytes during the postnatal period by regulating its downstream targets TARDBP and RBM38. This is the first study to demonstrate the role of CBX7 in regulation of cardiomyocyte proliferation, and CBX7 could be an important target for cardiac regeneration.
논문정보
- Research article
- 2023년 05월 (BRIC 등록일 2023-05-12)
- 국내(교신)+국외 연구진
- 의약학 > 재생의학
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