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 2014-2015
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)
Jennifer Jager, Ph.D. (Post-doc)
Bin Fang, Ph.D. (Post-doc)
Jill Marinis, Ph.D. (Post-doc)
Sean Armour, Ph.D. (Post-doc)
Lei Zhou, 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)
Samar Shah (Graduate Student)
Pegah Satabakhsh (Graduate Student)
Mei Lin (Graduate Student)
Erika Briggs (Research Specialst)
Lindsey Peed(Research Specialist)
Eric Chen (Research Specialist)
Cristina Lanzillotta (Research Specialist)
Joe Weaver (Lab Manager)
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.
Lewandowski SL, Janardhan HP, Smee KM, Bachman M, Sun Z, Lazar MA, Trivedi CM.: Histone deacetylase 3 modulates Tbx5 activity to regulate early cardiogenesis. Hum Mol Genet 23(14): 3801-9, Jul 2014.
Hoeksema MA, Gijbels MJ, Van den Bossche J, van der Velden S, Sijm A, Neele AE, Seijkens T, Stöger JL, Meiler S, Boshuizen MC, Dallinga-Thie GM, Levels JH, Boon L, Mullican SE, Spann NJ, Cleutjens JP, Glass CK, Lazar MA, de Vries CJ, Biessen EA, Daemen MJ, Lutgens E, de Winther MP.: Targeting macrophage Histone deacetylase 3 stabilizes atherosclerotic lesions. EMBO Mol Med Epub ahead of print, Jul 2014 Notes: 2014 Jul 9. pii: e201404170. doi: 10.15252/emmm.201404170. [Epub ahead of print]
Everett LJ, Lazar MA.: Nuclear receptor Rev-erbα: up, down, and all around. Trends Endocrinol Metab Epub ahead of print, Jul 2014 Notes: 2014 Jul 22. pii: S1043-2760(14)00122-2. doi: 10.1016/j.tem.2014.06.011. [Epub ahead of print] Review.
Lefterova MI, Haakonsson AK, Lazar MA, Mandrup S.: PPARγ and the global map of adipogenesis and beyond. Trends Endocrinol Metab 25(6): 293-302, Jun 2014.
Step SE, Lim HW, Marinis JM, Prokesch A, Steger DJ, You SH, Won KJ, Lazar MA.: Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers. Genes Dev 28(9): 1018-28, May 2014.
Jager J, O'Brien WT, Manlove J, Krizman EN, Fang B, Gerhart-Hines Z, Robinson MB, Klein PS, Lazar MA.: Behavioral changes and dopaminergic dysregulation in mice lacking the nuclear receptor Rev-erbα. Mol Endocrinol 28(4): 490-8, Apr 2014.
Lee S, Lee HC, Kwon YW, Lee SE, Cho Y, Kim J, Lee S, Kim JY, Lee J, Yang HM, Mook-Jung I, Nam KY, Chung J, Lazar MA, Kim HS.: Adenylyl cyclase-associated protein 1 is a receptor for human resistin and mediates inflammatory actions of human monocytes. Cell Metab. 19(3): 484-97, Mar 2014.
Lee JM, Wagner M, Xiao R, Kim KH, Feng D, Lazar MA, Moore DD. : Nutrient sensing nuclear receptors coordinate autophagy. Nature In press, 2014.
Soccio RE, Chen ER, Lazar MA.: Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes. Cell Metabolism 20: 573-591, 2014.
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Last updated: 10/24/2014
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