Epigenomic regulation of transcription and metabolism by nuclear receptors; mechanism of obesity-associated insulin resistance and diabetes; circadian regulation of metabolism
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 2016-2017
There are numerous potential projects that I would be pleased to discuss in person.
David Steger, Ph.D. (Research Assistant Professor)
Sean Armour, Ph.D. (Post-doc)
Romeo Papazyan, Ph.D. (Post-doc)
Victoria Nelson, Ph.D. (Post-doc)
Paul Titchenell, Ph.D. (Post-doc)
Dongyin Guan, Ph.D. (Post-doc)
David Hill, M.D., Ph.D. (Post-doc)
Zhenghui Li, Ph.D. (Post-doc)
Marine Adlanmerini, Ph.D. (Post-doc)
Wenxiang Hu, Ph.D. (Post-doc)
Matthew Emmett (Graduate Student)
Jarrett Remsberg (Graduate Student)
Yuxiang Zhang (Graduate Student)
Yong Hoon Kim (Graduate Student)
Patricia Borck (Graduate Student)
Erika Briggs (Research Specialist)
Lindsey Peed(Research Specialist)
Manashree Damle (Bioinformatics Research Specialist)
Yee Hoon Foong (Research Specialist)
Wesley Ho (Research Specialist)
Joe Weaver (Lab Manager)
Jager J, Wang F, Fang B, Lim HW, Peed LC, Steger DJ, Won KJ, Kharitonenkov A, Adams AC, Lazar MA.: The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-Specific Fibroblast Growth Factor 21 (FGF21) Signaling. J Biol Chem. Mar 2016 Notes: pii: jbc.M116.719120. [Epub ahead of print]
Wang Y, Frank DB, Morley MP, Zhou S, Wang X, Lu MM, Lazar MA, Morrisey EE.: HDAC3-Dependent Epigenetic Pathway Controls Lung Alveolar Epithelial Cell Remodeling and Spreading via miR-17-92 and TGF-β Signaling Regulation. Dev Cell 36(3): 303-15, Feb 2016.
Zhang L, He X, Liu L, Jiang M, Zhao C, Wang H, He D, Zheng T, Zhou X, Hassan A, Ma Z, Xin M, Sun Z, Lazar MA, Goldman SA, Olson EN, Lu QR.: Hdac3 Interaction with p300 Histone Acetyltransferase Regulates the Oligodendrocyte and Astrocyte Lineage Fate Switch. Dev Cell
36(3): 316-30, Feb 2016.
Gerhart-Hines Z, Lazar MA.: Rev-erbα and the circadian transcriptional regulation of metabolism. Diabetes Obes Metab. Suppl 1: 12-6, Sept 2015 Notes: doi: 10.1111/dom.12510.
PMID:26332963[PubMed - in process]
PMCID: PMC4562061 [Available on 2016-09-01]
Fang B, Lazar MA.: Dissecting the Rev-erbα Cistrome and the Mechanisms Controlling Circadian Transcription in Liver. Cold Spring Harb Symp Quant Biol. Page: pii: 027508. [Epub ahead of print] Sept 2015 Notes: PMID: 26370410
Altman BJ, Hsieh AL, Sengupta A, Krishnanaiah SY, Stine ZE, Walton ZE, Gouw AM, Venkataraman A, Li B, Goraksha-Hicks P, Diskin SJ, Bellovin DI, Simon MC, Rathmell JC, Lazar MA, Maris JM, Felsher DW, Hogenesch JB, Weljie AM, Dang CV.: MYC Disrupts the Circadian Clock and Metabolism in Cancer Cells. Cell Metab
Sept 2015 Notes: pii: S1550-4131(15)00460-X. doi: 10.1016/j.cmet.2015.09.003. [Epub ahead of print]
Soccio RE, Chen ER, Rajapurkar SR, Safabakhsh P, Marinis JM, Dispirito JR, Emmett MJ, Briggs ER, Fang B, Everett LJ, Lim HW, Won KJ, Steger DJ, Wu Y, Civelek M, Voight BF, Lazar MA.: Genetic Variation Determines PPARγ Function and Anti-diabetic Drug Response In Vivo. Cell 162(1): 33-44, Jul 2015 Notes: doi: 10.1016/j.cell.2015.06.025.
Lim HW, Uhlenhaut NH, Rauch A, Weiner J, Hübner S, Hübner N, Won KJ, Lazar MA, Tuckermann J, Steger DJ.: Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo. Genome Res. 25(6): 836-44, Jun 2015 Notes: doi: 10.1101/gr.188581.114. Epub 2015 May 8.
Yuxiang Zhang, Bin Fang, Matthew J. Emmett, Manashree Damle, Zheng Sun, Dan Feng, Sean M. Armour, Jarrett R. Remsberg, Jennifer Jager, Raymond E. Soccio, David J. Steger, Mitchell A. Lazar : Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock. Science 348(6242): 1488-92, Jun 2015.
Gerhart-Hines Z, Lazar MA.: Circadian metabolism in the light of evolution. Endocr Rev. 36(3): 289-304, Jun 2015 Notes: doi: 10.1210/er.2015-1007. Epub 2015 Apr 30.
back to top
Last updated: 06/09/2016
The Trustees of the University of Pennsylvania