A calcineurin–Hoxb13 axis regulates growth mode of mammalian cardiomyocytes

Ngoc Uyen Nhi Nguyen, Diana C. Canseco, Feng Xiao, Yuji Nakada, Shujuan Li, Nicholas T. Lam, Shalini A. Muralidhar, Jainy J. Savla, Joseph A. Hill, Victor Le, Kareem A. Zidan, Hamed W. El-Feky, Zhaoning Wang, Mahmoud Salama Ahmed, Maimon E. Hubbi, Ivan Menendez-Montes, Jesung Moon, Shah R. Ali, Victoria Le, Elisa VillalobosMagid S. Mohamed, Waleed M. Elhelaly, Suwannee Thet, Chukwuemeka George Anene-Nzelu, Wilson Lek Wen Tan, Roger S. Foo, Xun Meng, Mohammed Kanchwala, Chao Xing, Jagoree Roy, Martha S. Cyert, Beverly A. Rothermel, Hesham A. Sadek

Research output: Contribution to journalArticle

Abstract

A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting cardiomyocytes1,2 and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest3. Here we report that Hoxb13 acts as a cofactor of Meis1 in postnatal cardiomyocytes. Cardiomyocyte-specific deletion of Hoxb13 can extend the postnatal window of cardiomyocyte proliferation and reactivate the cardiomyocyte cell cycle in the adult heart. Moreover, adult Meis1–Hoxb13 double-knockout hearts display widespread cardiomyocyte mitosis, sarcomere disassembly and improved left ventricular systolic function following myocardial infarction, as demonstrated by echocardiography and magnetic resonance imaging. Chromatin immunoprecipitation with sequencing demonstrates that Meis1 and Hoxb13 act cooperatively to regulate cardiomyocyte maturation and cell cycle. Finally, we show that the calcium-activated protein phosphatase calcineurin dephosphorylates Hoxb13 at serine-204, resulting in its nuclear localization and cell cycle arrest. These results demonstrate that Meis1 and Hoxb13 act cooperatively to regulate cardiomyocyte maturation and proliferation and provide mechanistic insights into the link between hyperplastic and hypertrophic growth of cardiomyocytes.

Original languageEnglish (US)
Pages (from-to)271-276
Number of pages6
JournalNature
Volume582
Issue number7811
DOIs
StatePublished - Jun 11 2020

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    Nguyen, N. U. N., Canseco, D. C., Xiao, F., Nakada, Y., Li, S., Lam, N. T., Muralidhar, S. A., Savla, J. J., Hill, J. A., Le, V., Zidan, K. A., El-Feky, H. W., Wang, Z., Ahmed, M. S., Hubbi, M. E., Menendez-Montes, I., Moon, J., Ali, S. R., Le, V., ... Sadek, H. A. (2020). A calcineurin–Hoxb13 axis regulates growth mode of mammalian cardiomyocytes. Nature, 582(7811), 271-276. https://doi.org/10.1038/s41586-020-2228-6