DOT1L regulates chamber-specific transcriptional networks during cardiogenesis and mediates postnatal cell cycle withdrawal

Paola Cattaneo (), Michael G. B. Hayes, Nina Baumgarten, Dennis Hecker, Sofia Peruzzo, Galip S. Aslan, Paolo Kunderfranco, Veronica Larcher, Lunfeng Zhang, Riccardo Contu, Gregory Fonseca, Simone Spinozzi, Ju Chen, Gianluigi Condorelli, Stefanie Dimmeler, Marcel H. Schulz, Sven Heinz, Nuno Guimarães-Camboa and Sylvia M. Evans ()
Additional contact information
Paola Cattaneo: University of California San Diego
Michael G. B. Hayes: University of California San Diego
Nina Baumgarten: Goethe University
Dennis Hecker: Goethe University
Sofia Peruzzo: Goethe University
Galip S. Aslan: Goethe University
Paolo Kunderfranco: IRCCS Humanitas Research Hospital
Veronica Larcher: Goethe University
Lunfeng Zhang: University of California San Diego
Riccardo Contu: University of California San Diego
Gregory Fonseca: McGill University
Simone Spinozzi: University of California San Diego
Ju Chen: University of California San Diego
Gianluigi Condorelli: Milan Unit, National Research Council of Italy
Stefanie Dimmeler: Goethe University
Marcel H. Schulz: Goethe University
Sven Heinz: University of California San Diego
Nuno Guimarães-Camboa: University of California San Diego
Sylvia M. Evans: University of California San Diego

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Mechanisms by which specific histone modifications regulate distinct gene networks remain little understood. We investigated how H3K79me2, a modification catalyzed by DOT1L and previously considered a general transcriptional activation mark, regulates gene expression during cardiogenesis. Embryonic cardiomyocyte ablation of Dot1l revealed that H3K79me2 does not act as a general transcriptional activator, but rather regulates highly specific transcriptional networks at two critical cardiogenic junctures: embryonic cardiogenesis, where it was particularly important for left ventricle-specific genes, and postnatal cardiomyocyte cell cycle withdrawal, with Dot1L mutants having more mononuclear cardiomyocytes and prolonged cardiomyocyte cell cycle activity. Mechanistic analyses revealed that H3K79me2 in two distinct domains, gene bodies and regulatory elements, synergized to promote expression of genes activated by DOT1L. Surprisingly, H3K79me2 in specific regulatory elements also contributed to silencing genes usually not expressed in cardiomyocytes. These results reveal mechanisms by which DOT1L successively regulates left ventricle specification and cardiomyocyte cell cycle withdrawal.

Date: 2022
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DOI: 10.1038/s41467-022-35070-2

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