SIN3 is a global transcriptional coregulator that governs expression of a large repertoire of gene targets. It is an important player in gene regulation, which can repress or activate diverse gene targets in a context-dependent manner. SIN3 is required for several vital biological processes such as cell proliferation, energy metabolism, organ development, and cellular senescence. The functional flexibility of SIN3 arises from its ability to interact with a large variety of partners through protein interaction domains that are conserved across species, ranging from yeast to mammals. Several isoforms of SIN3 are present in these different species that can perform common and specialized functions through interactions with distinct enzymes and DNA-binding partners. Although SIN3 has been well studied due to its wide-ranging functions and highly conserved interaction domains, precise roles of individual SIN3 isoforms have received less attention. In this review, we discuss the differences in structure and function of distinct SIN3 isoforms and provide possible avenues to understand the complete picture of regulation by SIN3.

By using a histone gene replacement platform in Drosophila, we show that interactions among multiple factors contribute to HLB formation, and that the large number of genes at the endogenous histone locus sequesters available factors from attenuated transgenic histone gene arrays, thereby preventing HLB formation and histone gene expression from these arrays.

SIN3 is a transcriptional corepressor that acts as a scaffold for a histone deacetylase (HDAC) complex. The SIN3 complex regulates various biological processes, including organ development, cell proliferation, and energy metabolism. Little is known, however, about the regulation of SIN3 itself. There are two major isoforms of Drosophila SIN3, 187 and 220, which are differentially expressed. Intrigued by the developmentally timed exchange of SIN3 isoforms, we examined whether SIN3 187 controls the fate of the 220 counterpart. Here, we show that in developing tissue, there is interplay between SIN3 isoforms: when SIN3 187 protein levels increase, SIN3 220 protein decreases concomitantly. SIN3 187 has a dual effect on SIN3 220. Expression of 187 leads to reduced 220 transcript, while also increasing the turnover of SIN3 220 protein by the proteasome. These data support the presence of a novel, inter-isoform-dependent mechanism that regulates the amount of SIN3 protein, and potentially the level of specific SIN3 complexes, during distinct developmental stages.Normal cell function requires precise and coordinated regulation of abundance, localization, and interaction of numerous proteins and associated factors. This systematic regulation is brought about by several synchronized processes that govern the production, subcellular location, and timely degradation of proteins. Key among these processes is the ubiquitin-proteasome system, which eliminates specific proteins at determined time points (1). Disturbance of the ubiquitin-proteasome system has serious consequences in cellular function that can directly cause cell death (2). This is especially true for controlling the steady-state levels of master regulatory proteins that regulate diverse transcriptional networks. Specific examples include the histone-modifying enzymes, which govern chromatin organization and thus regulate gene networks. Dysregulation of histone-modifying enzymes can be disastrous for the cell, because it not only leads to aberrant gene expression, but also affects genome stability (3).The SIN3 HDAC 2 complex, evolutionarily conserved from yeast to mammals, is one such important histone-modifying complex (4, 5). The protein SIN3 serves as a scaffold for the assembly of this complex (5). SIN3 is a master transcriptional regulator that, when deleted or mutated, causes embryonic lethality in Drosophila and mice (6 -9). Previous work from our laboratory showed that depletion of Drosophila SIN3 affects several biological processes, resulting in severe developmental defects, increased sensitivity to oxidative stress, and reduced life span (10 -12). Although many of the gene networks and biological processes regulated by SIN3 are known, the regulation of the SIN3 protein itself is poorly understood.In Drosophila, a single Sin3A gene gives rise to multiple SIN3 isoforms, SIN3 187, SIN3 190, and SIN3 220. These isoforms vary only at the C terminus due to the presence of unique C-terminal exons, form distinct HDAC complexes, are functionally non-redundant, ...

The SIN3 scaffolding protein is a conserved transcriptional regulator known to fine-tune gene expression. In Drosophila, there are two major isoforms of SIN3, SIN3 220 and SIN3 187, which each assemble into multi-subunit histone modifying complexes. The isoforms have distinct developmental expression patterns and non-redundant functions. Gene regulatory network analyses indicate that both isoforms affect genes encoding proteins in pathways such as the cell cycle and cell morphogenesis. Interestingly, the SIN3 187 isoform uniquely regulates a subset of pathways including post-embryonic development, phosphate metabolism and apoptosis. Target genes in the phosphate metabolism pathway include nuclear-encoded mitochondrial genes coding for proteins responsible for oxidative phosphorylation, important for energy metabolism. Here, we investigate the role of SIN3 isoforms in regulating energy metabolism and cell survival genes. We find that ectopic expression of SIN3 187 represses expression of several nuclear-encoded mitochondrial genes affecting production of ATP and generation of reactive oxygen species (ROS). Forced expression of SIN3 187 also activates several pro-apoptotic and represses a few anti-apoptotic genes. In the SIN3 187 expressing cells, these gene expression patterns are accompanied with an increased sensitivity to paraquat-mediated oxidative stress. These findings indicate that SIN3 187 influences the regulation of mitochondrial function, apoptosis and oxidative stress response in ways that are dissimilar from SIN3 220. The data suggest that the distinct SIN3 histone modifying complexes are deployed in different cellular contexts to maintain cellular homeostasis.