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TRIM35 Monoubiquitinates H2B in Cardiac Cells, Implications for Heart Failure.
Lorenzana-Carrillo, Maria Areli; Tejay, Saymon; Nanoa, Joseph; Huang, Guocheng; Liu, Yongsheng; Haromy, Alois; Zhao, Yuan Yuan; Mendiola Pla, Michelle; Bowles, Dawn E; Kinnaird, Adam; Michelakis, Evangelos D; Sutendra, Gopinath.
Afiliação
  • Lorenzana-Carrillo MA; Department of Medicine (M.A.L.C., S.T., J.N., Y.L., A.H., Y.Y.Z., E.D.M., G.S.), University of Alberta, Edmonton, Canada.
  • Tejay S; Cardiovascular Research Institute (M.A.L.C., S.T., J.N., Y.L., A.H., Y.Y.Z., E.D.M., G.S.), University of Alberta, Edmonton, Canada.
  • Nanoa J; Cancer Research Institute of Northern Alberta (M.A.L.C., S.T., J.N., G.H., A.K., G.S.), University of Alberta, Edmonton, Canada.
  • Huang G; Department of Medicine (M.A.L.C., S.T., J.N., Y.L., A.H., Y.Y.Z., E.D.M., G.S.), University of Alberta, Edmonton, Canada.
  • Liu Y; Cardiovascular Research Institute (M.A.L.C., S.T., J.N., Y.L., A.H., Y.Y.Z., E.D.M., G.S.), University of Alberta, Edmonton, Canada.
  • Haromy A; Cancer Research Institute of Northern Alberta (M.A.L.C., S.T., J.N., G.H., A.K., G.S.), University of Alberta, Edmonton, Canada.
  • Zhao YY; Department of Medicine (M.A.L.C., S.T., J.N., Y.L., A.H., Y.Y.Z., E.D.M., G.S.), University of Alberta, Edmonton, Canada.
  • Mendiola Pla M; Cardiovascular Research Institute (M.A.L.C., S.T., J.N., Y.L., A.H., Y.Y.Z., E.D.M., G.S.), University of Alberta, Edmonton, Canada.
  • Bowles DE; Cancer Research Institute of Northern Alberta (M.A.L.C., S.T., J.N., G.H., A.K., G.S.), University of Alberta, Edmonton, Canada.
  • Kinnaird A; Cancer Research Institute of Northern Alberta (M.A.L.C., S.T., J.N., G.H., A.K., G.S.), University of Alberta, Edmonton, Canada.
  • Michelakis ED; Department of Surgery (G.H., A.K.), University of Alberta, Edmonton, Canada.
  • Sutendra G; Department of Medicine (M.A.L.C., S.T., J.N., Y.L., A.H., Y.Y.Z., E.D.M., G.S.), University of Alberta, Edmonton, Canada.
Circ Res ; 135(2): 301-313, 2024 Jul 05.
Article em En | MEDLINE | ID: mdl-38860363
ABSTRACT

BACKGROUND:

The tumor suppressor and proapoptotic transcription factor P53 is induced (and activated) in several forms of heart failure, including cardiotoxicity and dilated cardiomyopathy; however, the precise mechanism that coordinates its induction with accessibility to its transcriptional promoter sites remains unresolved, especially in the setting of mature terminally differentiated (nonreplicative) cardiomyocytes.

METHODS:

Male and female control or TRIM35 (tripartite motif containing 35) overexpression adolescent (aged 1-3 months) and adult (aged 4-6 months) transgenic mice were used for all in vivo experiments. Primary adolescent or adult mouse cardiomyocytes were isolated from control or TRIM35 overexpression transgenic mice for all in vitro experiments. Adenovirus or small-interfering RNA was used for all molecular experiments to overexpress or knockdown, respectively, target genes in primary mouse cardiomyocytes. Patient dilated cardiomyopathy or nonfailing left ventricle samples were used for translational and mechanistic insight. Chromatin immunoprecipitation and DNA sequencing or quantitative real-time polymerase chain reaction (qPCR) was used to assess P53 binding to its transcriptional promoter targets, and RNA sequencing was used to identify disease-specific signaling pathways.

RESULTS:

Here, we show that E3-ubiquitin ligase TRIM35 can directly monoubiquitinate lysine-120 (K120) on histone 2B in postnatal mature cardiomyocytes. This epigenetic modification was sufficient to promote chromatin remodeling, accessibility of P53 to its transcriptional promoter targets, and elongation of its transcribed mRNA. We found that increased P53 transcriptional activity (in cardiomyocyte-specific Trim35 overexpression transgenic mice) was sufficient to initiate heart failure and these molecular findings were recapitulated in nonischemic human LV dilated cardiomyopathy samples.

CONCLUSIONS:

These findings suggest that TRIM35 and the K120Ub-histone 2B epigenetic modification are molecular features of cardiomyocytes that can collectively predict dilated cardiomyopathy pathogenesis.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2024 Tipo de documento: Article