Regulation of SETD7 Methyltransferase by SENP3 Is Crucial for Sarcomere Organization and Cachexia

Summary: Precise assembly of the sarcomere, a force-generating unit in striated muscles, is critical for muscle contraction. Defective sarcomere organization is linked to myopathies and cachexia. The molecular mechanisms concerning sarcomere assembly are poorly understood. Here, we report that the SUMO-specific isopeptidase SENP3 determines sarcomere assembly by specifically regulating the sarcomeric contractile myosin heavy-chain gene MyHC-II. The contractile ability of mature muscle cells is severely compromised in SENP3-depleted cells. Mechanistically, SENP3 is associated with the SETD7 histone methyltransferase and deSUMOylates SETD7. By recruiting SETD7 to MyHC-II, SENP3 promotes association of SETD7 with transcriptionally active RNA polymerase II and precludes the opposing methyltransferase Suv39h1. Strikingly, SENP3 is degraded in cachexia, characterized by dramatic loss of sarcomeric protein, particularly MyHC-II. SENP3 regulation of SETD7 is impaired in cachexia, leading to perturbed MyHC-II expression and disorganized sarcomeres. Our findings reveal an unanticipated role of SENP3 in sarcomere assembly and cachexia. : Nayak et al. define the SENP3-governed transcriptional program, which is crucial for correct sarcomere assembly and contractile function of striated muscle cells. The SENP3-mediated transcriptional mechanism is disrupted in cachexia-induced muscle atrophy, leading to sarcomere disorganization and loss of muscle function. Keywords: sarcomere organization, cachexia, SENP3, SUMOylation, SETD7, epigenetics