Description of Research Expertise:
Epigenomic regulation of transcription and metabolism by nuclear receptors; mechanism of obesity-associated insulin resistance and diabetes; circadian regulation of metabolism
Key words: diabetes, endocrinology, epigenomics, nuclear receptors, circadian rhythms
Description of Research
The Lazar laboratory is studying the transcriptional regulation of metabolism. We are particularly focused on the role played by nuclear receptors (NRs). In the absence of ligand, NRs bind to DNA and function as potent transcriptional repressors by recruiting corepressor complexes that include the chromatin modulating enzyme histone deacetylase 3 (HDAC3). We are studying the tissue-specific and physiological roles of the corepressor complexes using by combining genomic, genetic, proteomic, bioinformatic, and metabolic phenotyping approaches. We are especially interested in the circadian NR Rev-erb alpha, which utilizes the corepressor complex to potently repress transcription. Rev-erb alpha is a key repressive component of the circadian clock that coordinates metabolism and biological rhythms. We are also studying PPAR gamma, a nuclear receptor that is a master regulator of adipocyte (fat cell) differentiation. Ligands for PPAR gamma have potent antidiabetic activity, and thus PPAR gamma represents a key transcriptional link between obesity and diabetes. The molecular, cellular, and integrative biology of these factors are being studied in mice and humans. We also have discovered resistin, a novel hormone and target of PPAR gamma that is made by fat cells in rodents and by macrophages in humans, and are testing the hypothesis that resistin links metabolism to inflammation in human metabolic diseases.
Rotation Projects for 2017-2018
There are numerous potential projects that I would be pleased to discuss in person.
David Steger, Ph.D. (Research Assistant Professor)
Victoria Nelson, Ph.D. (Post-doc)
Dongyin Guan, Ph.D. (Post-doc)
David Hill, M.D., Ph.D. (Post-doc)
Marine Adlanmerini, Ph.D. (Post-doc)
Wenxiang Hu, Ph.D. (Post-doc)
Yehuda Shabtai, Ph.D. (Post-doc)
Pieterjan Dierickx, Ph.D., (Post-doc)
Chunjie Jiang, Ph.D., (Post-doc)
Yong Hoon Kim (Graduate Student)
Hannah Richter (Graduate Student)
Erika Briggs (Research Specialist)
Lindsey Peed (Research Specialist)
Kavya Chgireddy (Bioinformatics Research Specialist)
Wesley Ho (Research Specialist)
Ying Xiong (Research Specialist)
Joe Weaver (Lab Manager)
Armour SM, Remsberg JR, Damle M, Sidoli S, Ho WY, Li Z, Garcia BA: An HDAC3-PROX1 corepressor module acts on HNF4α to control hepatic triglycerides. Nat Commun 8 (549): 1-11,2017.
Zhang Y, Papazyan R, Damle M, Fang B, Jager J, Feng D, Peed LC, Guan D, Sun Z: The hepatic circadian clock fine-tunes the lipogenic response to feeding through RORα/γ. Genes Dev : 2017.
Emmett MJ, Lim HW, Jager J, Richter HJ, Adlanmerini M, Peed LC, Briggs ER, Steger DJ, Ma T, Sims CA, Baur JA, Pei L, Won KJ, Seale P, Gerhart-Hines Z: Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge. Nature 546 (7659): 544-548,2017.
Soccio RE, Li Z, Chen ER, Foong YH, Benson KK, Dispirito JR, Mullican SE, Emmett MJ, Briggs ER, Peed LC, Dzeng RK, Medina CJ, Jolivert JF, Kissig M, Rajapurkar SR, Damle M, Lim HW, Won KJ, Seale P, Steger DJ: Targeting PPARγ in the epigenome rescues genetic metabolic defects in mice. J Clin Invest 127 (4): 1451-1462,2017.
Soccio RE, Li Z, Chen ER, Foong YH, Benson K, DiSpirito, Mullican SE, Emmett MJ, Briggs ER, Peed LC, Dzeng RK, Medina-Jimenez C, Kissig M, Rajapurkar SR, Damle M, Lim H-W, Won KJ, Seale P, Steger DJ: Targeting PPARγ in the epigenome rescues genetic metabolic defects in mice. J Clin Invest 127 (2): 1451-1462,2017.
Maturing of the nuclear receptor family. J Clin Invest 127 (4): 1123-1125,2017.
Titchenell PM, Lazar MA: Unraveling the Regulation of Hepatic Metabolism by Insulin. Trends Endocrinol Metab S1043-2760 (17): 30039-5,2017.
Hong S, Zhou W, Fang B, Lu W, Loro E, Damle M, Ding G, Jager J, Zhang S, Zhang Y, Feng D, Chu Q, Dill BD, Molina H, Khurana TS, Rabinowitz JD, Lazar MA: Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion. Nature Medicine
23 (2): 223-234,2017.
Plikus MV, Guerrero-Juarez CF, Ito M, Li YR, Dedhia PH, Zheng Y, Shao M, Gay DL, Ramos R, Hsi TC, Oh JW, Wang X, Ramirez A, Konopelski SE, Elzein A, Wang A, Supapannachart RJ, Lee HL, Lim CH, Nace A, Guo A, Treffeisen E, Andl T, Ramirez RN, Murad R, Offermanns S, Metzger D, Chambon P, Widgerow AD, Tuan TL, Mortazavi A, Gupta RK, Hamilton BA, Millar SE, Seale P, Pear WS, Lazar MA: Regeneration of fat cells from myofibroblasts during wound healing. Science 355 (6326): 748-752,2017.
Papazyan R, Zhang Y: Genetic and epigenomic mechanisms of mammalian circadian transcription. Nat Struct Mol Biol.
23 (12): 1045-1052,2016.
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