Enzyme-catalyzed histone modifications (e.g. (de)acetylation, (de)phosphorylation, and (de)methylation) result in a unique set of chemical 'marks' that regulate chromatin function through mechanisms that remain a focus of intense study. The combinatorial nature of these posttranslational modifications (PTMs) give rise to a histone 'code' or 'language', which is interpreted by enzyme complexes to mediate transcriptional responses. Importantly, these chromatin-modifying complexes have evolved to use co-substrates that are major metabolites linked to essential metabolic pathways, a fact eliciting the possibility that chromatin modifying enzymes exquisitely 'sense' metabolite levels (like acetyl-CoA, NAD+, SAM, 02, α-KG.) and respond accordingly, modifying specific chromatin loci for the appropriate response in gene expression. This proposal will investigate how metabolism and key epi-metabolite levels regulates epigenetic programs by controlling the activity of specific acetyltransferases, deacetylases, methyltransferases, and demethylases. In this proposal, we will investigate the hypothesis that epi-metabolite levels and the metabolic enzymes that produce these are intimately connected to chromatin modifying enzymes and that this link is a fundamental regulatory mechanism for controlling specific gene expression programs. To accomplish these goals, three aims are proposed: 1.) to determine how short-chain fatty acids produced from gut microbiota affect epigenetic control of gene expression in the host, 2) to determine the role of nuclear acetyl-CoA synthetase in controlling histone and non-histone protein acetylation, and 3.) to elucidate how SAM (S-adenosyl methionine) synthesis in the nucleus leads to maintenance of repressive epigenetic marks during metabolic stress. These integrated studies will provide a deep molecular understanding of the connections between metabolites acetyl-CoA and S-adenosyl methionine, and the dynamic regulation of chromatin modifications (acetylation and methylation) that drive both normal and stress-response pathways of gene expression.