The Mammalian Sin3 Proteins Are Required for Muscle Development and Sarcomere Specification

Abstract

The highly related mammalian Sin3A and Sin3B proteins provide a versatile platform for chromatinmodifying activities. Sin3-containing complexes play a role in gene repression through deacetylation of nucleosomes. Here, we explore a role for Sin3 in myogenesis by examining the phenotypes resulting from acute somatic deletion of both isoforms in vivo and from primary myotubes in vitro. Myotubes ablated for Sin3A alone, but not Sin3B, displayed gross defects in sarcomere structure that were considerably enhanced upon simultaneous ablation of both isoforms. Massively parallel sequencing of Sin3A-and Sin3B-bound genomic loci revealed a subset of target genes directly involved in sarcomere function that are positively regulated by Sin3A and Sin3B proteins. Both proteins were coordinately recruited to a substantial number of genes. Interestingly, depletion of Sin3B led to compensatory increases in Sin3A recruitment at certain target loci, but Sin3B was never found to compensate for Sin3A loss. Thus, our analyses describe a novel transcriptional role for Sin3A and Sin3B proteins associated with maintenance of differentiated muscle cells.

Sin3a regulates epithelial progenitor cell fate during lung development

“…Furthermore, our data suggest that Sin3a LOF cannot be functionally compensated for by presence of the related Sin3 family member Sin3b. These findings are consistent with previous publications suggesting that Sin3a also serves as scaffold protein for other histone modification complexes such as those involved in histone demethylation (Gajan et al, 2016) and that Sin3b has functions that only partially overlap with those of Sin3a, but are not redundant (Das et al, 2013;McDonel et al, 2012;van Oevelen et al, 2010).…”

“…This core complex also transiently associates with other regulatory proteins including Rb1 and chromatin regulatory enzymes to control gene expression (Kadamb et al, 2013;Silverstein and Ekwall, 2005). In addition to the transcriptional repression activity of the Sin3-Hdac complex, growing evidence suggests that Sin3 might also function to activate transcription of certain target genes in different organisms, including yeast and Drosophila, as well as mammalian systems such as mouse muscle development, mouse embryonic fibroblast and mouse embryonic stem cells (Baltus et al, 2009;Dannenberg et al, 2005;Das et al, 2013;Lin et al, 2005;Ruiz-Roig et al, 2010;van Oevelen et al, 2010;Yoshimoto et al, 1992), which would be consistent with the observation that Sin3 could also serve as a scaffold protein for the histone demethylase dKDM5/LID (Gajan et al, 2016). Thus, these studies suggest that Sin3 modulates transcriptional activity by serving as a scaffold protein able to coordinate multiple histone modification activities, including deacetylation and demethylation in a context-dependent manner.…”

ArabidopsisPaired Amphipathic Helix Proteins SNL1 and SNL2 Redundantly Regulate Primary Seed Dormancy via Abscisic Acid–Ethylene Antagonism Mediated by Histone Deacetylation

“…Stephan and Koch (2009) found that Sin3 and HDAC Rpd3 were both recruited to promoters of SBF (Swi4/Swi6)-regulated genes (CLN1, CLN2, and PCL1) in yeast. van Oevelen et al (2008van Oevelen et al ( , 2010 showed by ChIP assay that SIN3 directly impacts acetylation levels downstream of the transcriptional start site of target genes in mouse. Although ChIP assays for direct interaction between SNL1 and ethylene/ABA genes did not function in our hands, we speculate that the differentially expressed genes with altered histone acetylation level in the snl1 snl2 mutant could be the target genes of SNL1 or SNL2.…”

The chromatin-associated Sin3B protein is required for hematopoietic stem cell functions in mice

“…[9][10][11] Sin3B is a noncatalytic scaffold protein that serves as a core component for various histone deacetylase (HDAC) transcriptional repressor complexes, which are recruited to genomic loci via the interaction with sequencespecific transcription factors. 11,12 We have also recently demonstrated that a Sin3B-containing complex regulates postinitiation transcriptional events, through its interaction with chromatin readers.…”