John M. Denu

The Denu Lab Website

Education

• 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

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• Yang Z, Qian S, Scheid RN, Lu L, Chen X, Liu R, Du X, Lv X, Boersma MD, Scalf M, Smith LM, Denu JM, Du J, Zhong X (2018) EBS is a bivalent histone reader that regulates floral phase transition in Arabidopsis. Nat. Genet. : View Abstract · Pubmed Record

• Kuznetsov VI, Haws SA, Fox CA, Denu JM (2018) General method for rapid purification of native chromatin fragments. J. Biol. Chem. 293(31):12271-12282 (PMC6078465)

• Zhang XS, Li J, Krautkramer KA, Badri M, Battaglia T, Borbet TC, Koh H, Ng S, Sibley RA, Li Y, Pathmasiri W, Jindal S, Shields-Cutler RR, Hillmann B, Al-Ghalith GA, Ruiz VE, Livanos A, van ‘t Wout AB, Nagalingam N, Rogers AB, Sumner SJ, Knights D, Denu JM, Li H, Ruggles KV, Bonneau R, Williamson RA, Rauch M, Blaser MJ (2018) Antibiotic-induced acceleration of type 1 diabetes alters maturation of innate intestinal immunity. Elife 7: (PMC6085123)

• Qian S, Lv X, Scheid RN, Lu L, Yang Z, Chen W, Liu R, Boersma MD, Denu JM, Zhong X, Du J (2018) Dual recognition of H3K4me3 and H3K27me3 by a plant histone reader SHL. Nat Commun 9(1):2425 (PMC6013494)

• Ferrer CM, Alders M, Postma AV, Park S, Klein MA, Cetinbas M, Pajkrt E, Glas A, van Koningsbruggen S, Christoffels VM, Mannens MMAM, Knegt L, Etchegaray JP, Sadreyev RI, Denu JM, Mostoslavsky G, van Maarle MC, Mostoslavsky R (2018) An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality. Genes Dev. 32(5-6):373-388 (PMC5900711)

• Rhoads TW, Burhans MS, Chen VB, Hutchins PD, Rush MJP, Clark JP, Stark JL, McIlwain SJ, Eghbalnia HR, Pavelec DM, Ong IM, Denu JM, Markley JL, Coon JJ, Colman RJ, Anderson RM (2018) Caloric Restriction Engages Hepatic RNA Processing Mechanisms in Rhesus Monkeys. Cell Metab. 27(3):677-688.e5 (PMC5844481)

• Dhillon RS, Denu JM (2017) Using comparative biology to understand how aging affects mitochondrial metabolism. Mol. Cell. Endocrinol. 455:54-61

• Krautkramer KA, Dhillon RS, Denu JM, Carey HV (2017) Metabolic programming of the epigenome: host and gut microbial metabolite interactions with host chromatin. Transl Res 189:30-50 (PMC5659875)

• Lee JH, Yang B, Lindahl AJ, Damaschke N, Boersma MD, Huang W, Corey E, Jarrard DF, Denu JM (2017) Identifying Dysregulated Epigenetic Enzyme Activity in Castrate-Resistant Prostate Cancer Development. ACS Chem. Biol. 12(11):2804-2814

• Sanders D, Qian S, Fieweger R, Lu L, Dowell JA, Denu JM, Zhong X (2017) Histone Lysine-to-Methionine Mutations Reduce Histone Methylation and Cause Developmental Pleiotropy. Plant Physiol. 173(4):2243-2252 (PMC5373047)

• Deota S, Chattopadhyay T, Ramachandran D, Armstrong E, Camacho B, Maniyadath B, Fulzele A, Gonzalez-de-Peredo A, Denu JM, Kolthur-Seetharam U (2017) Identification of a Tissue-Restricted Isoform of SIRT1 Defines a Regulatory Domain that Encodes Specificity. Cell Rep 18(13):3069-3077 (PMC5545126)

• Krautkramer KA, Kreznar JH, Romano KA, Vivas EI, Barrett-Wilt GA, Rabaglia ME, Keller MP, Attie AD, Rey FE, Denu JM (2016) Diet-Microbiota Interactions Mediate Global Epigenetic Programming in Multiple Host Tissues. Mol. Cell 64(5):982-992 (PMC5227652)

• Su Z, Wang F, Lee JH, Stephens KE, Papazyan R, Voronina E, Krautkramer KA, Raman A, Thorpe JJ, Boersma MD, Kuznetsov VI, Miller MD, Taverna SD, Phillips GN, Denu JM (2016) Reader domain specificity and lysine demethylase-4 family function. Nat Commun 7:13387 (PMC5114558)

• Morris BA, Burkel B, Ponik SM, Fan J, Condeelis JS, Aguirre-Ghiso JA, Castracane J, Denu JM, Keely PJ (2016) Collagen Matrix Density Drives the Metabolic Shift in Breast Cancer Cells. EBioMedicine 13:146-156 (PMC5264313)

• Rensvold JW, Krautkramer KA, Dowell JA, Denu JM, Pagliarini DJ (2016) Iron Deprivation Induces Transcriptional Regulation of Mitochondrial Biogenesis. J. Biol. Chem. 291(40):20827-20837 (PMC5076495)

• Gregg T, Poudel C, Schmidt BA, Dhillon RS, Sdao SM, Truchan NA, Baar EL, Fernandez LA, Denu JM, Eliceiri KW, Rogers JD, Kimple ME, Lamming DW, Merrins MJ (2016) Pancreatic β-Cells From Mice Offset Age-Associated Mitochondrial Deficiency With Reduced KATP Channel Activity. Diabetes 65(9):2700-10 (PMC5001174)

• Wang X, Yuan ZF, Fan J, Karch KR, Ball LE, Denu JM, Garcia BA (2016) A Novel Quantitative Mass Spectrometry Platform for Determining Protein O-GlcNAcylation Dynamics. Mol. Cell Proteomics 15(7):2462-75 (PMC4937517)

• Hullinger R, Li M, Wang J, Peng Y, Dowell JA, Bomba-Warczak E, Mitchell HA, Burger C, Chapman ER, Denu JM, Li L, Puglielli L (2016) Increased expression of AT-1/SLC33A1 causes an autistic-like phenotype in mice by affecting dendritic branching and spine formation. J. Exp. Med. 213(7):1267-84 (PMC4925020)

• Baeza J, Smallegan MJ, Denu JM (2016) Mechanisms and Dynamics of Protein Acetylation in Mitochondria. Trends Biochem. Sci. 41(3):231-44 (PMC4783225)

• Su Z, Denu JM (2016) Reading the Combinatorial Histone Language. ACS Chem. Biol. 11(3):564-74

• Yu W, Denu RA, Krautkramer KA, Grindle KM, Yang DT, Asimakopoulos F, Hematti P, Denu JM (2016) Loss of SIRT3 Provides Growth Advantage for B Cell Malignancies. J. Biol. Chem. 291(7):3268-79 (PMC4751373)

• Kugel S, Feldman JL, Klein MA, Silberman DM, Sebastián C, Mermel C, Dobersch S, Clark AR, Getz G, Denu JM, Mostoslavsky R (2015) Identification of and Molecular Basis for SIRT6 Loss-of-Function Point Mutations in Cancer. Cell Rep 13(3):479-88 (PMC4618237)

• Krautkramer KA, Reiter L, Denu JM, Dowell JA (2015) Quantification of SAHA-Dependent Changes in Histone Modifications Using Data-Independent Acquisition Mass Spectrometry. J. Proteome Res. 14(8):3252-62 (PMC4564294)

• Su Z, Denu JM (2015) MARCC (Matrix-Assisted Reader Chromatin Capture): An Antibody-Free Method to Enrich and Analyze Combinatorial Nucleosome Modifications. Curr Protoc Mol Biol 111:21.32.1-21 (PMC4848750)

• Feldman JL, Dittenhafer-Reed KE, Kudo N, Thelen JN, Ito A, Yoshida M, Denu JM (2015) Kinetic and Structural Basis for Acyl-Group Selectivity and NAD(+) Dependence in Sirtuin-Catalyzed Deacylation. Biochemistry 54(19):3037-3050 (PMC4470489)

• Dittenhafer-Reed KE, Richards AL, Fan J, Smallegan MJ, Fotuhi Siahpirani A, Kemmerer ZA, Prolla TA, Roy S, Coon JJ, Denu JM (2015) SIRT3 mediates multi-tissue coupling for metabolic fuel switching. Cell Metab. 21(4):637-46 (PMC4393847)

• Fan J, Krautkramer KA, Feldman JL, Denu JM (2015) Metabolic regulation of histone post-translational modifications. ACS Chem. Biol. 10(1):95-108 (PMC4407823)