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.
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)
Rashid Mehmood, Ph.D., (Post-doc)
Mohit Midha, Ph.D., (Post-doc)
Delaine Zayas-Bazan Burgos (Graduate Student)
Isaac Celwyn (Research Specialist)
Maria Krieg (Research Specialist)
Lily Melink (Research Specialist)
Yifan Liu (Research Specialist)
Michelle Burrows (Lab Manager)
Lazar MA.: Tugs-of-war in science. J Clin Invest. 132(20): e165312, Oct 2022 Notes: doi: 10.1172/JCI165312.
Lazar MA, Magnuson MA, Kaestner KH: Franz Matschinsky, MD (1931–2022): Paragon of Scientific Rigor and Curiosity Who Discovered Glucokinase as the Pancreatic Glucose Sensor. Diabetes
71: 2078–2083, Oct 2022 Notes: https://doi.org/10.2337/dbi22-0017.
Hu W, Lazar MA.: Modelling metabolic diseases and drug response using stem cells and organoids. Nat Rev Endocrinol. Page: 1-16, Sep 2022 Notes: doi: 10.1038/s41574-022-00733-z.
Xiao T, Langston PK, Muñoz-Rojas AR, Jayewickreme T, Lazar MA, Benoist C, Mathis D.: Tregs in visceral adipose tissue up-regulate circadian-clock expression to promote fitness and enforce a diurnal rhythm of lipolysis. Sci Immunol. 7(75): eabl7641, Sep 2022 Notes: doi: 10.1126/sciimmunol.abl7641.
Richter HJ, Hauck AK, Batmanov K, Inoue SI, So BN, Kim M, Emmett MJ, Cohen RN, Lazar MA.: Balanced control of thermogenesis by nuclear receptor corepressors in brown adipose tissue. Proc Natl Acad Sci U S A 119(33): e2205276119, Aug 2022 Notes: doi: 10.1073/pnas.2205276119.
Woodie LN, Oral KT, Krusen BM, Lazar MA.: The Circadian Regulation of Nutrient Metabolism in Diet-Induced Obesity and Metabolic Disease. Nutrients 14(15): 3136, Jul 2022 Notes: doi: 10.3390/nu14153136.
Chen Z, Ye Z, Soccio RE, Nakadai T, Hankey W, Zhao Y, Huang F, Yuan F, Wang H, Cui Z, Sunkel B, Wu D, Dzeng RK, Thomas-Ahner JM, Huang THM, Clinton SK, Huang J, Lazar MA, Jin VX, Roeder RG, Wang Q.: Phosphorylated MED1 links transcription recycling and cancer growth. Nucleic Acids Res 50(8): 4450-4463, May 2022 Notes: doi: 10.1093/nar/gkac246.
Santoleri D, Lim HW, Emmett MJ, Stoute J, Gavin MJ, Sostre-Colón J, Uehara K, Welles JE, Liu KF, Lazar MA, Titchenell PM.: Global-run on sequencing identifies Gm11967 as an Akt-dependent long noncoding RNA involved in insulin sensitivity. iScience 25(6): 104410, May 2022.
Guan D, Lazar MA.: Circadian Regulation of Gene Expression and Metabolism in the Liver. Semin Liver Dis. 42(2): 113-121, Mar 2022 Notes: doi: 10.1055/a-1792-4240.
Hu W, Jiang C, Kim M, Xiao Y, Richter HJ, Guan D, Zhu K, Krusen BM, Roberts AN, Miller J, Steger DJ, Lazar MA.: Isoform-specific functions of PPARγ in gene regulation and metabolism. Genes Dev. 36(5-6): 300-312, Mar 2022 Notes: doi: 10.1101/gad.349232.121.
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Last updated: 11/30/2022
The Trustees of the University of Pennsylvania