Cellular responses to available macronutrients and extra-cellular signals rely on the unique epigenetic state of the cell, defined by a layer of biochemical information above the genome that dictates specific gene expression. The epigenome consists of DNA sequence-dependent proteins, non-coding RNAs, DNA methylation and histone post-translation modifications (PTMs) such as lysine acetylation and methylation. The latter two mechanisms are catalyzed by enzymes that must ‘interpret’ incoming signals, ‘read’ the existing epigenetic landscape and ‘respond’ appropriately. Enzymes that modify histones and non-histone proteins such as methyltransferases, demethylases, acetyltransferases and deacetylases use central metabolites (S-adenosyl methionine, SAM; a-ketoglutarate, acetyl-CoA and nicotinamide adenine dinucleotide, NAD+, respectively) as co-substrates. New evidence suggests that fluctuation in such epi-metabolites caused by diet, environment, microbiota and genetics can drive PTM dynamics, however the relevant mechanisms remain unclear in most cases. In this seminar, Professor Denu will highlight recent work to understand how histone lysine methylation is impacted by metabolite availability. Histone methyltransferases (HMTs) rely on the metabolite S-adenosylmethionine (SAM) as the sole methyl donor, resulting in altered in vivo activity during SAM depletion. The cellular responses and long term consequences to low SAM levels will be discussed.
John Denu is Professor of Biomolecular Chemistry at the University of Wisconsin-Madison and Epigenetics Theme Leader, Wisconsin Institute for Discovery. His laboratory focuses on the roles of reversible protein modifications, in particular histone modifications, that are involved in modulating signal transduction, chromatin dynamics, and gene expression. John is a key opinion leader in the field of small molecule sirtuin modulators; his lab has both discovered small-molecule ligands and significantly advanced the field from early controversies to the molecular elucidation of mechanisms of action for a synthetic, natural product, and in vivo agonists of multiple family members of sirtuins. John is a Fellow of the AAAS and has received numerous honors including the American Cancer Association Young Investigator and Research Scholar Awards, and the NIH Merit Award.
Moderation: Professor Dr. Michael Lammers (Greifswald)