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 and epigenomic 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, and bioinformatics, and metabolic phenotyping approaches. We are especially interested in the circadian NR Rev-erbα, which utilizes the corepressor complex to potently repress transcription. Rev-erbα is a key repressive component of the circadian clock that senses heme levels to coordinate metabolism and biological rhythms. We are also studying PPARγ, a nuclear receptor that is a master regulator of adipocyte (fat cell) differentiation. Ligands for PPARγ have potent antidiabetic activity, and thus PPARγ represents a key transcriptional link between obesity and diabetes. The molecular, cellular, and integrative biology of these factors are being studied in mouse and human cell lines as well as in mouse knockin and knockout models. We also have discovered resistin, a novel hormone and target of PPARγ that is made and secreted by fat cells in rodents and by macrophages in humans. We have demonstrated that resistin regulates insulin responsiveness, and are now using mice humanized for resistin to test the hypothesis that resistin links metabolism to inflammation in human metabolic diseases.
Rotation Projects for 2015-2016
There are numerous potential projects that I would be pleased to discuss in person.
David Steger, Ph.D. (Research Assistant Professor)
Ray Soccio, M.D., Ph.D. (Instructor in Medicine)
Bin Fang, Ph.D. (Post-doc)
Sean Armour, Ph.D. (Post-doc)
Romeo Papazyan, Ph.D. (Post-doc)
Satoshi Yoshino, Ph.D. (Post-doc)
Victoria Nelson, Ph.D. (Post-doc)
Sonia Step (Graduate Student)
Matthew Emmett (Graduate Student)
Jarrett Remsberg (Graduate Student)
Yuxiang Zhang (Graduate Student)
Yong Hoon Kim (Graduate Student)
Mei Lin (Graduate Student)
Erika Briggs (Research Specialst)
Lindsey Peed(Research Specialist)
Cristina Lanzillotta (Research Specialist)
Joe Weaver (Lab Manager)
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 Page: DOI: 10.1126/science.aab3021 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.
Harms MJ, Lim HW, Ho Y, Shapira SN, Ishibashi J, Rajakumari S, Steger DJ, Lazar MA, Won KJ, Seale P.: PRDM16 binds MED1 and controls chromatin architecture to determine a brown fat transcriptional program. Genes Dev. 29(3): 298-307, Feb 2015.
Jang JC, Chen G, Wang SH, Barnes MA, Chung JI, Camberis M, Le Gros G, Cooper PJ, Steel C, Nutman TB, Lazar MA, Nair MG.: Macrophage-derived human resistin is induced in multiple helminth infections and promotes inflammatory monocytes and increased parasite burden. PLoS Pathog. 11(1:e1004579), Jan 2015 Notes: doi: 10.1371/journal.ppat.1004579. eCollection 2015 Jan.
Lee JM, Wagner M, Xiao R, Kim KH, Feng D, Lazar MA, Moore DD. : Nutrient sensing nuclear receptors coordinate autophagy. Nature
516(7529): 112-5, Dec 2014.
Fang B, Everett LJ (co-first author), Jager J (co-first author), Briggs E, Armour S, Feng D, Roy A, Gerhart-Hines Z, Sun Z, Lazar MA. : Circadian enhancers coordinate multiple phases of rhythmic gene expression in vivo. Cell
159(5): 1140-52, Nov 2014.
Gardini A, Baillat D, Cesaroni M, Hu D, Marinis JM, Wagner EJ, Lazar MA, Shilatifard A, Shiekhattar R.: Integrator regulates transcriptional initiation and pause release following activation. Mol Cell. 56(1): 128-39, Oct 2014.
Gardini A, Baillat D, Cesaroni M, Hu D, Marinis JM, Wagner EJ, Lazar MA, Shilatifard A, Shiekhattar R. : Integrator regulates activator-dependent transcriptional elongation by recruiting super elongation complex. Molecular Cell
56(1): 128-139, Oct 2014.
Soccio RE, Chen ER, Lazar MA.: Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes. Cell Metabolism
20(4): 573-591, Oct 2014.
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Last updated: 06/05/2015
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