ABSTRACT
Stra13 and Sharp-1 are transcriptional repressors that share domain structure similarity with members of the basic helix-loop-helix-Orange subfamily. In contrast to other members that include Hes and Hey proteins, transcriptional repression mediated by Stra13 and Sharp-1 does not involve recruitment of the corepressor Groucho. Both proteins undergo sumoylation at evolutionarily conserved sites, and this posttranslational modification serves as a platform for association with chromatin-modifying enzymes including histone deacetylases and histone methyltransferases. In addition to being widely expressed during embryonic development and in adult tissues, the expression of both genes is induced by a number of stimuli. Loss-of-function and gain-of-function studies have demonstrated their function in cellular differentiation and regeneration, in regulation of circadian rhythms, immune homeostasis, and metabolism. Given their diverse physiological functions in several tissues, it is not surprising that deregulated expression of Stra13 and Sharp-1 is apparent in human pathologies. Here, we review our current understanding of their cellular functions that suggest a requirement in maintenance of tissue homeostasis.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , DNA-Binding Proteins/metabolism , Homeodomain Proteins/genetics , Nuclear Proteins/metabolism , Transcription Factors/genetics , Animals , Apoptosis/genetics , Cell Cycle Checkpoints , Cell Differentiation , DNA Repair/physiology , DNA-Binding Proteins/genetics , Gene Expression Regulation, Developmental , Histone Deacetylases/metabolism , Histone Methyltransferases , Histone-Lysine N-Methyltransferase/metabolism , Homeodomain Proteins/metabolism , Humans , Hypoxia/metabolism , Immune System/metabolism , Mice , Muscle, Skeletal/cytology , Muscle, Skeletal/physiology , Neoplasms/metabolism , Neoplasms/pathology , Nuclear Proteins/genetics , Sumoylation , Transcription Factors/metabolismABSTRACT
Skeletal muscle cells have served as a paradigm for understanding mechanisms leading to cellular differentiation. The proliferation and differentiation of muscle precursor cells require the concerted activity of myogenic regulatory factors including MyoD. In addition, chromatin modifiers mediate dynamic modifications of histone tails that are vital to reprogramming cells toward terminal differentiation. Here, we provide evidence for a unique dimension to epigenetic regulation of skeletal myogenesis. We demonstrate that the lysine methyltransferase G9a is dynamically expressed in myoblasts and impedes differentiation in a methyltransferase activity-dependent manner. In addition to mediating histone H3 lysine-9 di-methylation (H3K9me2) on MyoD target promoters, endogenous G9a interacts with MyoD in precursor cells and directly methylates it at lysine 104 (K104) to constrain its transcriptional activity. Mutation of K104 renders MyoD refractory to inhibition by G9a and enhances its myogenic activity. Interestingly, MyoD methylation is critical for G9a-mediated inhibition of myogenesis. These findings provide evidence of an unanticipated role for methyltransferases in cellular differentiation states by direct posttranslational modification of a transcription factor.
