Chaubal and Pile Epigenetics & Chromatin (2018) 11:17 https://doi.org/10.1186/s13072-018-0188-y Epigenetics & Chromatin REVIEW Open Access Same agent, diferent messages: insight into transcriptional regulation by SIN3 isoforms Ashlesha Chaubal and Lori A. Pile* Abstract SIN3 is a global transcriptional coregulator that governs expression of a large repertoire of gene targets. It is an impor- tant 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 develop- ment, and cellular senescence. The functional fexibility 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 diferent 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 diferences in structure and function of distinct SIN3 isoforms and provide possible avenues to understand the complete picture of regulation by SIN3. Keywords: SIN3 isoforms, Transcription, Chromatin, Posttranslational modifcation Background thereby amenable to gene expression. Factors that regu- Te basic requirement for survival of any cell, whether late the level of acetylation of histone proteins are an prokaryotic or eukaryotic, is the accurate expression excellent example of this phenomenon. Enzymes that of appropriate genes. In prokaryotes, failure to express acetylate specifc amino acid residues on N-terminal tails important metabolic enzyme or stress response genes of histone proteins, histone acetyltransferases (HATs), can afect the organism’s ability to respond to environ- can activate gene transcription, whereas enzymes that mental stimuli and ultimately result in cell death. In remove the acetyl mark from these residues, histone multicellular organisms, regulation of gene expression is deacetylases (HDACs), typically promote gene silenc- critical not only for response to external stimuli but also ing. Te SIN3 histone-modifying complex is one such to ensure timely expression of cell type-specifc genes important player that regulates various biological pro- for the development of diferent tissues and organs. Te cesses through activation or repression of a large reper- presence of chromatin, a complex of the DNA molecule toire of target genes. SIN3 was frst discovered in 1987 wrapped around a core of histone proteins, is key for by two independent research groups studying mating gene regulation in eukaryotes. type switching in Saccharomyces cerevisiae [1, 2]. Both Precise regulation of spatiotemporal gene expres- groups identifed SIN3 as a negative regulator of the HO sion is orchestrated by the action of many vital players (homothallic switching) endonuclease, which is essen- that govern the organization and compaction of chro- tial for mating type switching in yeast. In the decade fol- matin. Chromatin-modifying complexes can determine lowing its discovery, SIN3 was identifed in independent whether the chromatin is compact and therefore refrac- genetic screens under fve diferent aliases, UME4, RPD1, tory to transcription factor binding, or is more accessible, GAM2, CPE1, and SDS16, primarily as a negative regula- tor of transcription [3–7]. In 1997, three separate studies showed that SIN3 is associated with the histone dea- *Correspondence: [email protected] cetylases HDAC1/2 in a multi-protein complex [8–10]. Department of Biological Sciences, Wayne State University, Detroit, MI 48202, USA As deacetylated histones have long been correlated with © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chaubal and Pile Epigenetics & Chromatin (2018) 11:17 Page 2 of 11 transcription inactivity, the SIN3 complex is canonically Te corepressor activity of SIN3 is commonly attrib- regarded as a corepressor complex [11]. uted to its association with the deacetylase enzymes Accumulating evidence, however, points to a dual role HDAC1 and HDAC2. Te ways in which the complex of the SIN3 complex in the regulation of transcription may function to activate gene transcription, however, are (Table 1). Te transcriptional profle of a SIN3 deletion not understood. Tere are a number of potential molecu- yeast strain showed upregulation of 173 transcripts con- lar mechanisms in which SIN3 complex activity could frming the role of Sin3 in gene repression [12]. In addi- lead to gene activation. One possibility is that the HDAC1 tion, 269 transcripts were downregulated in the absence component of the complex deacetylates a DNA-binding of Sin3, suggesting a possible role in gene activation. A transcription factor, which alters the DNA-binding capa- genome-wide study performed using a Drosophila cell bility or protein interactions of the transcription factor. culture system comparing wild type and Sin3A RNA Two examples of transcription factors demonstrated to interference-mediated knockdown cells showed a simi- be regulated by acetylation are YYI, which can function lar result to that of yeast mutants [13]. Out of the 13,137 as both a repressor and as an activator, and Foxo1 [21, genes that were tested by microarray analysis, SIN3 was 22]. Te full list of possible transcription factor substrates required for the repression of 364 genes, whereas 35 for HDAC1 has yet to be elucidated. A second possible genes were activated by SIN3. Further evidence for the mechanism in which the SIN3 complex could activate dual role of SIN3 came from a gene expression analysis in gene transcription is by infuencing nucleosome occu- another important model system. Loss of SIN3 in mouse pancy around transcription start sites. Chen et al. [23] fbroblast cells resulted in diferential expression of 1308 found that yeast Rpd3-containing complexes have chap- genes, out of which 977 were upregulated and 331 were erone activity and impact nucleosome assembly in vitro. downregulated [14]. Te data presented in that work principally focused on Although the initial transcriptome studies revealed the role of the complex in repression. In their discussion, several gene targets that were downregulated upon however, the authors speculate that nucleosome remode- loss of SIN3, the role of SIN3 in gene activation was not ling could either facilitate or repress transcription of gene well understood and was commonly attributed to indi- targets. In addition to histone modifcation, DNA meth- rect efects. Activation of transcription by SIN3 could ylation infuences transcription activity. SIN3 interacts conceivably result from a secondary efect; yet, several with the DNA demethylase TET1, and the two proteins gene-specifc studies suggest otherwise. NANOG is a colocalize at a number of genomic sites [19]. It is pos- transcription factor critical for maintaining the pluripo- sible that SIN3 complex association with TET1 impacts tent state in embryonic stem cells [15]. During embryonic local DNA methylation levels, which then leads to tran- stem cell diferentiation, phosphorylated p53 suppresses scription activation. Much work remains for the future Nanog expression by recruiting SIN3A to the Nanog pro- to determine the specifc mechanisms in which a single moter [16]. Conversely, under proliferating conditions, complex can have opposite efects. the SIN3A/HDAC complex is recruited to the Nanog Te ability of SIN3 to repress or activate gene tran- promoter leading to Sox2-mediated stimulation of Nanog scription is likely due to its interaction with a large reper- expression [17]. Tus, SIN3A regulates Nanog expression toire of DNA-binding factors. Te SIN3 protein contains either positively or negatively, in a context-dependent six highly conserved regions (Fig. 1). Tese were initially manner. SIN3A also plays a dual role in regulation of STAT described as four paired amphipathic alpha-helix motifs transcriptional activity [18]. STAT1 and STAT3 perform (PAH1-4), a histone deacetylase interaction domain opposing functions in the regulation of cell proliferation (HID) and a highly conserved region (HCR) [24, 25]. and survival. SIN3A interacts with STAT3 and acts as a Recent updates in terminology refer to the region con- repressor of STAT3 activity. In contrast, SIN3A is required taining the PAH4 domain and the HCR as the Sin3a_C for the transcription of ISGF3 (STAT1:STAT2:IRF9) com- superfamily domain (Fig. 1). Tese domains, conserved plex-regulated genes. Studies performed in human kidney from yeast to mammals, are essential for interaction with embryonic cells and Drosophila S2 cells provide a clearer the core components of the SIN3 complex and other picture of the direct role of SIN3 in gene transcription, by interacting