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 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)
Kim YH, Lazar MA.: Transcriptional Control of Circadian Rhythms and Metabolism: A Matter of Time and Space. Endocr Rev. 41(5): bnaa014, Oct 2020.
Guan D, Xiong Y, Trinh TM, Xiao Y, Hu W, Jiang C, Dierickx P, Jang C, Rabinowitz JD, Lazar MA.: The hepatocyte clock and feeding control chronophysiology of multiple liver cell types. Science. 369(6509): 1388-1394, Sept 2020 Notes: doi: 10.1126/science.aba8984. Online ahead of print.
Nguyen HCB, Adlanmerini M, Hauck AK, Lazar MA.: Dichotomous engagement of HDAC3 activity governs inflammatory responses. Nature 584(7820): 286-290, Aug 2020 Notes: doi: 10.1038/s41586-020-2576-2. Online ahead of print.
Szigety KM, Liu F, Yuan CY, Moran DJ, Horrell J, Gochnauer HR, Cohen RN, Katz JP, Kaestner KH, Seykora JT, Tobias JW, Lazar MA, Xu M, Millar SE.: HDAC3 ensures stepwise epidermal stratification via NCoR/SMRT-reliant mechanisms independent of its histone deacetylase activity. Genes Dev. 34(13-14): 973-988, Jul 2020.
Angueira AR, Shapira SN, Ishibashi J, Sampat S, Sostre-Colón J, Emmett MJ, Titchenell PM, Lazar MA, Lim HW, Seale P.: Early B Cell Factor Activity Controls Developmental and Adaptive Thermogenic Gene Programming in Adipocytes. Cell Rep. 30(9): 2869-2878.e4, Mar 2020.
Guan D, Lazar MA.: Shining light on dark matter in the genome. Proc Natl Acad Sci U S A. 116(50): 24919-24921, Dec 2019.
Kuo T, Kraakman MJ, Damle M, Gill R, Lazar MA, Accili D.: Identification of C2CD4A as a human diabetes susceptibility gene with a role in β cell insulin secretion. Proc Natl Acad Sci U S A. 116(40): 20033-20042, Oct 2019 Notes: pii: 201904311. doi: 10.1073/pnas.1904311116. [Epub ahead of print]
Adlanmerini M, Carpenter BJ, Remsberg JR, Aubert Y, Peed LC, Richter HJ, Lazar MA.: Circadian lipid synthesis in brown fat maintains murine body temperature during chronic cold. Proc Natl Acad Sci U S A. 116(37): 18691-18699, Sept 2019.
Jaitin DA, Adlung L, Thaiss CA, Weiner A, Li B, Descamps H, Lundgren P, Bleriot C, Liu Z, Deczkowska A, Keren-Shaul H, David E, Zmora N, Eldar SM, Lubezky N, Shibolet O, Hill DA, Lazar MA, Colonna M, Ginhoux F, Shapiro H, Elinav E, Amit I.: Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner. Cell 178(3): 686-698.e14, Jul 2019 Notes: pii: S0092-8674(19)30625-7. doi: 10.1016/j.cell.2019.05.054. [Epub ahead of print]
Dierickx P, Emmett MJ, Jiang C, Uehara K, Liu M, Adlanmerini M, Lazar MA.: SR9009 has REV-ERB-independent effects on cell proliferation and metabolism. Proc Natl Acad Sci U S A
116(25): 12147-12152, Jun 2019 Notes: doi: 10.1073/pnas.1904226116. Epub 2019 May 24.
back to top
Last updated: 09/18/2020
The Trustees of the University of Pennsylvania