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 2021-2022
There are numerous potential projects that I would be pleased to discuss in person.
Pieterjan Dierickx, Ph.D., (Post-doc)
Amy Hauck, Ph.D., (Post-doc)
Yang Xiao, Ph.D., (Post-doc)
Kun Zhu, Ph.D., (Post-doc)
Lauren Woodie, Ph.D., (Post-doc)
Michael Tackenberg, Ph.D., (Post-doc)
Shin-Ichi Inoue, Ph.D., (Post-doc)
Tiffany Fleet, M.D., Ph.D., (Post-doc)
Yoon Jeong Park, Ph.D., (Post-doc)
Hannah Richter (Graduate Student)
Delaine Zayas-Bazan Burgos (Graduate Student)
Brianna Krusen (Research Specialist)
Bryce Carpenter (Research Specialist)
Alexander Tom (Research Specialist)
Isaac Celwyn (Research Specialist)
Joe Weaver (Lab Manager)
Dierickx P, Zhu K, Carpenter BJ, Jiang C, Vermunt MW, Xiao Y, Luongo TS, Yamamoto T, Martí-Pàmies Í, Mia S, Latimer M, Diwan A, Nguyen HC, Blober GA, Kelly DP, Pei L, Baur JA, Young ME, Lazar MA. : Circadian REV-ERBs repress E4bp4 to activate NAMPT-dependent NAD+ biosynthesis and sustain cardiac function. Nature Cardiovascular Research 1(1): 45–58, Dec 2021 Notes: doi: https://doi.org/10.1038/s44161-021-00001-9.
Adlanmerini M, Krusen BM, Nguyen HCB, Teng CW, Woodie LN, Tackenberg MC, Geisler CE, Gaisinsky J, Peed LC, Carpenter BJ, Hayes MR, Lazar MA.: REV-ERB nuclear receptors in the suprachiasmatic nucleus control circadian period and restrict diet-induced obesity. Sci Adv. 7(44): eabh200, Oct 2021 Notes: doi: 10.1126/sciadv.abh2007. Epub 2021 Oct 27.
Mitchell A Lazar: Novel biomedical research must not be a work of fiction. J Clin Invest 131(18): e150827, Sep 2021.
Hu W, Jiang C, Kim M, Yang W, Zhu K, Guan D, Lv W, Xiao Y, Wilson JR, Rader DJ, Pui CH, Relling MV, Lazar MA.: Individual-specific functional epigenomics reveals genetic determinants of adverse metabolic effects of glucocorticoids. Cell Metab. 33(8): 1592-1609, Aug 2021.
Xiao Y, Kim M, Lazar MA.: Nuclear receptors and transcriptional regulation in non-alcoholic fatty liver disease. Mol Metab 50: 101119, Aug 2021 Notes: doi: 10.1016/j.molmet.2020.101119.
Guan D, Lazar MA.: Interconnections between circadian clocks and metabolism. J Clin Invest 131(15): e148278, Aug 2021.
Gillen AE, Fu R, Riemondy KA, Jager J, Fang B, Lazar MA, Martin SL.: Liver Transcriptome Dynamics During Hibernation Are Shaped by a Shifting Balance Between Transcription and RNA Stability. Front Physiol 12: 662132, May 2021 Notes: doi: 10.3389/fphys.2021.662132. eCollection 2021.
Shabtai Y, Nagaraj NK, Batmanov K, Cho YW, Guan Y, Jiang C, Remsberg J, Forrest D, Lazar MA.: A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in the liver. Genes Dev 35(5-6): 367-378, Mar 2021 Notes: doi: 10.1101/gad.345686.120.
Adlanmerini M, Nguyen HC, Krusen BM, Teng CW, Geisler CE, Peed LC, Carpenter BJ, Hayes MR, Lazar MA.: Hypothalamic REV-ERB nuclear receptors control diurnal food intake and leptin sensitivity in diet-induced obese mice. J Clin Invest 131(1): e140424, Jan 2021 Notes: doi: 10.1172/JCI140424.
Fang B, Guan D, Lazar MA.: Using GRO-Seq to Measure Circadian Transcription and Discover Circadian Enhancers. Methods Mol Biol 2130: 127-148, 2021 Notes: doi: 10.1007/978-1-0716-0381-9_10.
back to top
Last updated: 01/13/2022
The Trustees of the University of Pennsylvania