John M. Denu
Credentials: Mechanisms of chromatin dynamics, epigenetic, metabolism and signaling
Position title: Professor (also Epigenetics Theme Leader, Wisconsin Institute for Discovery)
Phone: (608) 316-4341
2178 Wisconsin Institute for Discovery
330 N. Orchard St. Madison, WI 53715
• B.S. 1988, University of Wisconsin-Madison
• Ph.D. 1993, Texas A & M University (Paul F. Fitzpatrick)
• Postdoctoral 1993-96, University of Michigan Medical School (Jack E. Dixon)
Honors & Awards
• Robert A. Welch Research Fellow (1992-93)
• National Research Service Award (1993-96)
• Young Investigator Award (American Cancer Association 1997-2000)
• Research Scholar Award (American Cancer Association 2001-2004)
• Romnes Fellow, University of Wisconsin (2006)
• Epigenetics Theme Director, Wisconsin Institute for Discovery (2009)
• Elected Fellow of the AAAS, 2011
• NIH Merit Award,2013
• Kellett Mid-Career Faculty Award (2016)
There are currently three major areas of research in the group:
1.) Writing, reading and editing a molecular language/code
What are the basic biochemical principles that govern epigenetic information written onto histones? Currently, we are addressing the fundamental hypothesis that the combinatorial nature of nucleosomal PTM (post-translational modification) states are specifically recognized and acted upon by enzyme complexes containing multivalent readers. These 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 largely unknown mechanisms. We and others have proposed that combinatorial posttranslational modifications (PTMs) give rise to a histone ‘code’ or ‘language’, which is interpreted by enzyme complexes to mediate transcriptional responses (e.g., activation or repression). We employ numerous biochemical approaches to investigate the existence of a functional histone code involving enzyme-catalyzed PTMs.
2.) Linking metabolism with the epigenome
Chromatin remodeling enzymes rely on co-enzymes derived from metabolic pathways, suggesting coordination between nuclear events and metabolic networks. Investigations are underway to understand the link between metabolism and the regulation of epigenetic mechanisms. We are testing the hypothesis that certain chromatin modifying complexes have evolved to exquisitely ‘sense’ metabolite levels and respond accordingly, modifying specific chromatin loci for altered gene expression.
3.) Sirtuins and reversible protein acetylation
Accumulating evidence suggests that reversible protein-lysine is a major regulatory mechanism that controls non-histone protein function. With the recent mass-spectral cataloging of ~1000 acetylation sites on protein lysine residues comes the exciting challenge of assigning functional roles to specific acetylation sites, identifying the acetyltransferases and deacetylases that regulate acetylation levels, and elucidating the physiological cause and effect of specific acetylation. In only a few cases have the acetyltransferases and deacetylases been identified. Also, there is a scarcity of molecular understanding of the functional consequences of reversible protein acetylation. Sirtuins are a conserved family of NAD+-dependent protein deacetylases that have emerged as important players in modulating protein acetylation. Compelling genetic evidence implicates sirtuins in genome maintenance, metabolism, cell survival, and lifespan. The NAD+-dependence suggests that specific protein deacetylation is inextricably linked to metabolism. We are examining the central hypothesis that reversible protein acetylation is a major regulatory mechanism for controlling diverse metabolic processes, and that at the molecular level, site-specific acetylation alters the intrinsic activity of targeted proteins.
Perform a customized PubMed literature search for John M. Denu
- Rigby, M.J., N.S. Orefice, A.J. Lawton, M. Ma, S.L. Shapiro, S.Y. Yi, I.A. Dieterich, A. Frelka, H.N. Miles, R.A. Pearce, J.P.J. Yu, L. Li, J.M. Denu, and L. Puglielli. (2022). Increased expression of SLC25A1/CIC causes an autistic-like phenotype with altered neuron morphology. Brain : a journal of neurology, 145: 500-516.
- Liu, W.H., R.E. Miner, B.N. Albaugh, G.E. Ananiev, S.A. Wildman, and J.M. Denu. (2022). Discovery and Mechanism of Small Molecule Inhibitors Selective for the Chromatin-Binding Domains of Oncogenic UHRF1. Biochemistry, 61: 354-366.
- Murphy, M.E., A. Narasimhan, A. Adrian, A. Kumar, C.L. Green, C. Soto-Palma, C. Henpita, C. Camell, C.S. Morrow, C.Y. Yeh, C.E. Richardson, C.M. Hill, D.L. Moore, D.W. Lamming, E.R. McGregor, H.A. Simmons, H.H. Pak, H. Bai, J.M. Denu, J. Clark, J. Simcox, K. Chittimalli, K. Dahlquist, K.A. Lee, M. Calubag, M. Bouska, M.J. Yousefzadeh, M. Sonsalla, R. Babygirija, R. Yuan, T. Tsuji, T. Rhoads, V. Menon, Y.P. Jarajapu, and Y. Zhu. (2022). Metabolism in the Midwest: research from the Midwest Aging Consortium at the 49 Annual Meeting of the American Aging Association. GeroScience, 44: 39-52.
- Taylor, J.R., J.G. Wood, E. Mizerak, S. Hinthorn, J. Liu, M. Finn, S. Gordon, L. Zingas, C. Chang, M.A. Klein, J.M. Denu, V. Gorbunova, A. Seluanov, J.D. Boeke, J.M. Sedivy, and S.L. Helfand. (2022). Sirt6 regulates lifespan in Drosophila melanogaster. Proceedings of the National Academy of Sciences of the United States of America, 119: .
- Cheng, H., Y.A. Qin, R. Dhillon, J. Dowell, J.M. Denu, and M.E. Pamenter. (2022). Metabolomic Analysis of Carbohydrate and Amino Acid Changes Induced by Hypoxia in Naked Mole-Rat Brain and Liver. Metabolites, 12: .
- Rigby, M.J., N.S. Orefice, A.J. Lawton, M. Ma, S.L. Shapiro, S.Y. Yi, I.A. Dieterich, A. Frelka, H.N. Miles, R.A. Pearce, J.P.J. Yu, L. Li, J.M. Denu, and L. Puglielli. (2022). SLC13A5/sodium-citrate co-transporter overexpression causes disrupted white matter integrity and an autistic-like phenotype. Brain communications, 4: fcac002.
- Thomas, S.P., and J.M. Denu. (2021). Short-chain fatty acids activate acetyltransferase p300. eLife, 10: .
- Pak, H.H., S.A. Haws, C.L. Green, M. Koller, M.T. Lavarias, N.E. Richardson, S.E. Yang, S.N. Dumas, M. Sonsalla, L. Bray, M. Johnson, S. Barnes, V. Darley-Usmar, J. Zhang, C.E. Yen, J.M. Denu, and D.W. Lamming. (2021). Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice. Nature metabolism, 3: 1327-1341.
- Rigby, M.J., A.J. Lawton, G. Kaur, V.C. Banduseela, W.E. Kamm, A. Lakkaraju, J.M. Denu, and L. Puglielli. (2021). Endoplasmic reticulum acetyltransferases Atase1 and Atase2 differentially regulate reticulophagy, macroautophagy and cellular acetyl-CoA metabolism. Communications biology, 4: 454.
- Albaugh, B.N., and J.M. Denu. (2021). Catalysis by protein acetyltransferase Gcn5. Biochimica et biophysica acta. Gene regulatory mechanisms, 1864: 194627.