Loss of YTHDF2 Alters the Expression of m6A-Modified Myzap and Causes Adverse Cardiac Remodeling

Volha A Golubeva; Lisa E Dorn; Christopher J Gilbert; Charles P Rabolli; Anindhya Sundar Das; Vishmi S Wanasinghe; Roland Veress; Dmitry Terentyev; Federica Accornero

doi:10.1016/j.jacbts.2023.03.012

Loss of YTHDF2 Alters the Expression of m⁶A-Modified Myzap and Causes Adverse Cardiac Remodeling

JACC Basic Transl Sci. 2023 Jun 21;8(9):1180-1194. doi: 10.1016/j.jacbts.2023.03.012. eCollection 2023 Sep.

Authors

Volha A Golubeva¹, Lisa E Dorn¹, Christopher J Gilbert¹, Charles P Rabolli¹, Anindhya Sundar Das¹, Vishmi S Wanasinghe¹, Roland Veress¹, Dmitry Terentyev¹, Federica Accornero¹

Affiliation

¹ Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.

Abstract

How post-transcriptional regulation of gene expression, such as through N⁶-methyladenosine (m⁶A) messenger RNA methylation, impacts heart function is not well understood. We found that loss of the m⁶A binding protein YTHDF2 in cardiomyocytes of adult mice drove cardiac dysfunction. By proteomics, we found myocardial zonula adherens protein (MYZAP) within the top up-regulated proteins in knockout cardiomyocytes. We further demonstrated that YTHDF2 binds m⁶A-modified Myzap messenger RNA and controls its stability. Cardiac overexpression of MYZAP has been associated with cardiomyopathy. Thus, our findings provide an important new mechanism for the YTHDF2-dependent regulation of this target and therein its novel role in the maintenance of cardiac homeostasis.

Keywords: RNA binding protein; hypertrophy; post-transcriptional gene regulation.

Abstract

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