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, ?-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.
This proposal explores how metabolism and environmental factors influence gene expression through epigenetic mechanisms. It is well established that human phenotypes and susceptibility to disease are products of genetics and external environmental factors; however, the molecular basis for their interplay remains elusive. The proposed work will determine how major metabolic pathways are linked to epigenetic modulation of gene expression. consolidating metabolic information in cellular decision-making.
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| Qian, Shuiming; Lv, Xinchen; Scheid, Ray N et al. (2018) Dual recognition of H3K4me3 and H3K27me3 by a plant histone reader SHL. Nat Commun 9:2425 |
| Kuznetsov, Vyacheslav I; Haws, Spencer A; Fox, Catherine A et al. (2018) General method for rapid purification of native chromatin fragments. J Biol Chem 293:12271-12282 |
| Yang, Zhenlin; Qian, Shuiming; Scheid, Ray N et al. (2018) EBS is a bivalent histone reader that regulates floral phase transition in Arabidopsis. Nat Genet 50:1247-1253 |
| Krautkramer, Kimberly A; Rey, Federico E; Denu, John M (2017) Chemical signaling between gut microbiota and host chromatin: What is your gut really saying? J Biol Chem 292:8582-8593 |
| Sanders, Dean; Qian, Shuiming; Fieweger, Rachael et al. (2017) Histone Lysine-to-Methionine Mutations Reduce Histone Methylation and Cause Developmental Pleiotropy. Plant Physiol 173:2243-2252 |
| Krautkramer, Kimberly A; Dhillon, Rashpal S; Denu, John M et al. (2017) Metabolic programming of the epigenome: host and gut microbial metabolite interactions with host chromatin. Transl Res 189:30-50 |
| Su, Zhangli; Denu, John M (2016) Reading the Combinatorial Histone Language. ACS Chem Biol 11:564-74 |
| Su, Zhangli; Wang, Fengbin; Lee, Jin-Hee et al. (2016) Reader domain specificity and lysine demethylase-4 family function. Nat Commun 7:13387 |
| Morris, Brett A; Burkel, Brian; Ponik, Suzanne M et al. (2016) Collagen Matrix Density Drives the Metabolic Shift in Breast Cancer Cells. EBioMedicine 13:146-156 |
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