John M. Denu

John M. Denu Headshot


(Also Epigenetics Theme Director, Wisconsin Institute for Discovery)

2178 Wisconsin Institute for Discovery (WID)

330 North Orchard St. Madison, WI 53715

The Denu Lab Website

Phone: (608) 316-4341




• 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)

Research Interests
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.


Publications of Note

Perform a customized PubMed literature search for Dr. Denu.

• Baeza J, Smallegan MJ, Denu JM. Site-specific reactivity of nonenzymatic lysine acetylation.
ACS Chem Biol. 2015 Jan 16;10(1):122-8. doi: 10.1021/cb500848p. PubMed PMID: 25555129;
PubMed Central PMCID: PMC4301072.

• Fan J, Krautkramer KA, Feldman JL, Denu JM. Metabolic regulation of histone post-translational
modifications. ACS Chem Biol. 2015 Jan 16;10(1):95-108. doi: 10.1021/cb500846u. PubMed
PMID: 25562692.

• Baeza J, Dowell JA, Smallegan JM, Fan J, Amador-Noguez D, Khan Z, and Denu JM. Stoichiometry of site-specific lysine acetylation in an entire proteome. J. Biol. Chem. published June 10, 2014 as doi:10.1074/jbc.M114.581843

• Sahar S, Masubuchi S, Eckel-Mahan K, Vollmer S, Galla L, Ceglia N, Masri S, Barth TK,
Grimaldi B, Oluyemi O, Astarita G, Hallows WC, Piomelli D, Imhof A, Baldi P, Denu JM, Sassone-Corsi P. Circadian control of fatty acid elongation by SIRT1 protein-mediated deacetylation of acetyl-coenzyme A synthetase 1. J Biol Chem. 2014 Feb 28;289(9):6091-7

• Su Z, Boersma MD, Lee JH, Oliver SS, Liu S, Garcia BA, Denu JM. ChIP-less analysis of
chromatin states. Epigenetics Chromatin. 2014 Apr 24;7:7.

• Prolla TA, Denu JM. NAD+ deficiency in age-related mitochondrial dysfunction. Cell Metab. 2014
Feb 4;19(2):178-80.

• Gough SM, Lee F, Yang F, Walker RL, Zhu YJ, Pineda M, Onozawa M, Chung YJ, Bilke S,
Wagner EK, Denu JM, Ning Y, Xu B, Wang GG, Meltzer PS, Aplan PD. NUP98-PHF23 is a chromatin-modifying oncoprotein that causes a wide array of leukemias sensitive to inhibition of PHD histone reader function. Cancer Discov. 2014 May;4(5):564-77.

• Wickert LE, Blanchette JB, Waldschmidt NV, Bertics PJ, Denu JM, Denlinger LC, Lenertz LY.
The C-terminus of human nucleotide receptor P2X7 is critical for receptor oligomerization and N-
linked glycosylation. PLoS One. 2013 May 14;8(5).

• Zhou X, Fan LX, Sweeney WE Jr, Denu JM, Avner ED, Li X. Sirtuin 1 inhibition delays cyst
formation in autosomal-dominant polycystic kidney disease. J Clin Invest. 2013 Jul
1;123(7):3084-98. doi: 10.1172/JCI64401.

• Still AJ, Floyd BJ, Hebert AS, Bingman CA, Carson JJ, Gunderson DR, Dolan BK, Grimsrud PA, Dittenhafer-Reed KE, Stapleton DS, Keller MP, Westphall MS, Denu JM, Attie AD, Coon JJ,
Pagliarini DJ. Quantification of mitochondrial acetylation dynamics highlights prominent sites of
metabolic regulation. J Biol Chem. 2013 Sep 6;288(36):26209-19.

• Peek CB, Affinati AH, Ramsey KM, Kuo HY, Yu W, Sena LA, Ilkayeva O, Marcheva B,
Kobayashi Y, Omura C, Levine DC, Bacsik DJ, Gius D, Newgard CB, Goetzman E, Chandel NS, Denu JM, Mrksich M, Bass J. Circadian clock NAD+ cycle drives mitochondrial oxidative metabolism in mice. Science. 2013 Nov 1;342(6158):1243417.

• Feldman JL, Baeza J, Denu JM. Activation of the Protein Deacetylase SIRT6 by Long-chain Fatty
Acids and Widespread Deacylation by Mammalian Sirtuins. J Biol Chem. 2013 Oct

• Denu JM, Gottesfeld JM. Minireview series on sirtuins: from biochemistry to health and disease.
J Biol Chem. 2012 Dec 14;287(51):42417-8.

• Dominy JE Jr, Lee Y, Jedrychowski MP, Chim H, Jurczak MJ, Camporez JP, Ruan HB, Feldman J,
Pierce K, Mostoslavsky R, Denu JM, Clish CB, Yang X, Shulman GI, Gygi SP, Puigserver P.
The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis. Mol Cell. 2012 Dec 28;48(6):900-13.

• Hebert AS, Dittenhafer-Reed KE, Yu W, Bailey D, Selen ES, Boersma MD, Carson JJ, Tonelli M,
Balloon, A, Assadi-Porter F, Pagliarini DJ, Prolla TA, Westphall MS, Roy S, *Denu JM, and
Coon JJ. Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. Molecular Cell. 2013 Jan 10;49(1):186-99.
(*corresponding author)

• Feldman JL, Dittenhafer-Reed KE, Denu JM. Sirtuin Catalysis and Regulation. J Biol Chem. 2012
Dec 14;287(51):42419-27. Review.

• Wagner EK, Albaugh BN, Denu JM. High-throughput strategy to identify inhibitors of histone-
binding domains. Methods Enzymol. 2012;512:161-85. PubMed PMID: 22910207.

• Wagner EK, Nath N, Flemming R, Feltenberger JB, Denu JM. Identification and characterization
of small molecule inhibitors of a PHD finger. Biochemistry. 2012 Oct 16;51(41):8293-306.

• Oliver SS, Musselman CA, Srinivasan R, Svaren JP, Kutateladze TG, Denu JM. Multivalent
Recognition of Histone Tails by the PHD Fingers of CHD5. Biochemistry. 2012 Aug

• Yu W, Dittenhafer-Reed KE, Denu JM. SIRT3 protein deacetylates isocitrate dehydrogenase 2
(IDH2) and regulates mitochondrial redox status. J Biol Chem. 2012 Apr 20;287(17):14078-86. Epub 2012 Mar 13. PMCID: PMC3340192.

• Hallows WC, Yu W, Denu JM. Regulation of glycolytic enzyme phosphoglycerate mutase-1 by
Sirt1 protein-mediated deacetylation. J Biol Chem. 2012 Feb 3;287(6):3850-8. Epub 2011 Dec 7.
PubMed PMID: 22157007; PubMed Central PMCID: PMC3281715.