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)
Guan D, Xiong Y, Borck PC, Jang C, Doulias PT, Papazyan R, Fang B, Jiang C, Zhang Y, Briggs ER, Hu W, Steger D, Ischiropoulos H, Rabinowitz JD, Lazar MA.: Diet-Induced Circadian Enhancer Remodeling Synchronizes Opposing Hepatic Lipid Metabolic Processes. Cell.
174 (4): 831-842.e12,2018.
Nelson VL, Nguyen HCB, Garcìa-Cañaveras JC, Briggs ER, Ho WY, DiSpirito JR, Marinis JM, Hill DA, Lazar MA.: PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism. Genes Dev. 32 (15-16): 1035-1044,2018.
Zhang Y, Dallner OS, Nakadai T, Fayzikhodjaeva G, Lu YH, Lazar MA, Roeder RG, , Friedman JM.: A noncanonical PPARγ/RXRα-binding sequence regulates leptin expression in response to changes in adipose tissue mass.
Proc Natl Acad Sci U S A
[Epub ahead of print] : 2018.
Lazar MA.: Reversing the curse on PPARγ. J Clin Invest 128 (6): 2202-2204,2018.
Razzoli M, Emmett MJ, Lazar MA, Bartolomucci A.: β-Adrenergic receptors control
brown adipose UCP-1 tone and cold response without affecting its circadian
FASEB J. [Epub ahead of print] : 2018.
Borck PC, Batista TM, Vettorazzi JF, Soares GM, Lubaczeuski C, Guan D, Boschero AC, Vieira E, Lazar MA, Carneiro EM.: Nighttime light exposure enhances
Rev-erbα-targeting microRNAs and contributes to hepatic steatosis.
Metabolism 85 : 250-258,2018.
Hill DA, Lim HW, Kim YH, Ho WY, Foong YH, Nelson VL, Nguyen HCB, Chegireddy K, Kim J, Habertheuer A, Vallabhajosyula P, Kambayashi T, Won KJ, Lazar MA.: Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue.
Proc Natl Acad Sci U S A. 115 (22): E5096-E5105,2018.
Kim YH, Marhon SA, Zhang Y, Steger DJ, Won KJ, Lazar MA.: Rev-erbα dynamically
modulates chromatin looping to control circadian gene transcription.
Science 359 (6381): 1274-1277,2018.
Jang JC, Li J, Gambini L, Batugedara HM, Sati S, Lazar MA, Fan L, Pellecchia, M, Nair MG: Human resistin protects against endotoxic shock by blocking LPS-TLR4
Proc Natl Acad Sci U S A 114 (48): E10399-E10408,2017.
Poleshko A, Shah PP, Gupta M, Babu A, Morley MP, Manderfield LJ, Ifkovits JL, , Calderon D, Aghajanian H, Sierra-Pagán JE, Sun Z, Wang Q, Li L, Dubois NC, Morrisey EE, Lazar MA, Smith CL, Epstein JA, Jain R.: Genome-Nuclear Lamina
Interactions Regulate Cardiac Stem Cell Lineage Restriction.
Cell 171 (3): 573-587,2017.
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