The Transcriptional Corepressor SIN3 Directly Regulates Genes Involved in Methionine Catabolism and Affects Histone Methylation, Linking Epigenetics and Metabolism

Abstract

Chromatin modification and cellular metabolism are tightly connected. Chromatin modifiers regulate the expression of genes involved in metabolism and, in turn, the levels of metabolites. The generated metabolites are utilized by chromatin modifiers to affect epigenetic modification. The mechanism for this cross-talk, however, remains incompletely understood. The corepressor SIN3 controls histone acetylation through association with the histone deacetylase RPD3. The SIN3 complex is known to regulate genes involved in a number of metabolic processes. Here, we find that Drosophila SIN3 binds to the promoter region of genes involved in methionine catabolism and that this binding affects histone modification, which in turn influences gene expression. Specifically, we observe that reduced expression of SIN3 leads to an increase in S-adenosylmethionine (SAM), which is the major cellular donor of methyl groups for protein modification. Additionally, Sin3A knockdown results in an increase in global histone H3K4me3 levels. Furthermore, decreased H3K4me3 caused by knockdown of either SAM synthetase (Sam-S) or the histone methyltransferase Set1 is restored to near normal levels when SIN3 is also reduced. Taken together, these results indicate that knockdown of Sin3A directly alters the expression of methionine metabolic genes to increase SAM, which in turn leads to an increase in global H3K4me3. Our study reveals that SIN3 is an important epigenetic regulator directly connecting methionine metabolism and histone modification.

The Lid/KDM5 histone demethylase complex activates a critical effector of the oocyte-to-zygote transition

“…The conserved Sin3A protein scaffold interacts with the histone lysine deacetylase HDAC1 to form the core SIN3 histone deacetylase complex, which is generally considered as a transcriptional repressor [14]. The SIN3 complex regulates the expression of genes involved in a number of metabolic and developmental processes [15][16][17][18]. Interestingly, Lid and the largest Sin3A isoform were previously shown to physically and functionally interact [15,16,19,20], thus opening the possibility that these histone modifiers could control the same pathway leading to the formation of a diploid zygote.…”

Physical and functional interaction between SET1/COMPASS complex component CFP-1 and a Sin3 HDAC complex

“…Functions ascribed to Rpd3/Sin3 complexes are varied and appear to be context dependent. Although typically referred to as corepressor complexes due to the presence of a histone deacetylase subunit, Rpd3/Sin3 complexes have been associated with both activation and repression of gene expression (Cantor and David, 2017;Cheng et al, 2014;Halder et al, 2017;Lewis et al, 2016;Liu and Pile, 2016;Saha et al, 2016;Saunders et al, 2017;van Oevelen et al, 2008van Oevelen et al, , 2010. In addition, the yeast Rpd3/Sin3S complex has been shown to repress cryptic transcription initiation in transcribed regions and to suppress antisense transcription initiation at promoters (Carrozza et al 2005;Churchman and Weissman 2011).…”

Mitochondrial-epigenetic crosstalk in environmental toxicology

“…For example, the SIN3 histone deacetylase complex binds promoters of genes involved in methionine catabolism, which influence SAM production, which in turn influences nuclear histone methylation levels [66]. …”