TRIM35-Mediated Histone 2B Ubiquitination; An Epigenetic Modification that Reveals P53 Transcriptional Targets in Heart Failure

The tumor suppressor and pro-apoptotic transcription factor P53 is induced (and activated) in several forms of heart failure, including cardiotoxicity and dilated cardiomyopathy (DCM); 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 (non-replicative) cardiomyocytes.The E3-ubiquitin ligase TRIM35 can directly monoubiquitinate lysine-120 (K120) on histone 2B (H2B) in mature adult cardiomyocytes. This epigenetic modification was sufficient to promote chromatin remodeling, accessibility of P53 to its transcriptional 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 non-ischemic human LV DCM samples. These findings suggest that the K120Ub-H2B epigenetic modification could be a molecular feature (in cardiomyocytes) to predict initiation and progression of heart failure.