University of Pennsylvania
Division of Endocrinology, Diabetes & Metabolism
12-102 Smilow Translational Research Center
3400 Civic Center Boulevard
Philadelphia, PA 19104-5160
Tel: (215) 898-0198
Fax: (215) 898-5408
My laboratory focuses on the transcriptional and epigenomic regulation of metabolism by nuclear receptors and their coregulators. Our identification of the nuclear heme receptor Rev-erba and its corepressor complex, including histone deacetylase 3 (HDAC3), have uncovered fundamental principles of molecular clocks and the circadian regulation of metabolism, as well as the tissue-specificity of coregulator function and epigenomic modifications. Our pioneering studies of PPARg and adipocyte biology, including discovery of the hormone resistin, have linked basic mechanisms of gene transcription to physiology and metabolic diseases. This work has important implications for endocrinology, diabetes, and metabolism.
Discovery of Rev-erba and mechanism of repression by nuclear receptors. I discovered receptors for thyroid hormone as well as the orphan NR that we named Rev-erba that is the subject of this proposal. My lab demonstrated that Rev-erbs bind to a unique DNA sequence as a monomer and to a related site as a dimer. We were among the first to recognize that NRs have a ligand-independent repression function, and we discovered the CoRNR box motif which explains why corepressors bind to unliganded but not liganded forms of nuclear receptors. Most recently we discovered that Rev-erba represses transcription at the genome both directly and indirectly, i.e., independent of its DNA-binding domain. Together, our studies have demonstrated the mechanism and physiological significance of repression by Rev-erba and other NRs.
Nuclear Receptor Corepressor Complexes. My laboratory was first to purify an endogenous NR corepressor complex, and discovered the stoichiometric presence of the epigenome modifying enzyme HDAC3. We demonstrated that HDAC3 polypeptide itself has little intrinsic enzymatic activity, and its deacetylation function requires interaction with a region of NCoR or SMRT that we termed the DAD (“Deacetylase Activating Domain”), and that the catalytic activity of HDAC3 requires the DAD in vivo. We also generated NCoR mutant mice to show for the first time that corepressors and HDAC3 were critical for normal adult physiology. These studies have demonstrated the repression mechanisms and physiological functions of nuclear receptor corepressors.
PPARg in Adipose Biology. In 1994, we reported that PPARg is predominantly expressed in adipose tissue and induced during adipocyte differentiation. We found that phosphorylation regulates PPARg activity and in vivo insulin sensitivity, and that adipose PPARg is required for normal fat development in vivo. We were first to characterize the PPARg cistrome in mouse adipocytes, and demonstrate a role for nearby binding of C/EBPa. We have also shown that antidiabetic TZD ligands activate PPARg bound at enhancers, while transrepression is due redistribution of coactivators away from enhancer sites controlled by other factors. Most recently we demonstrated that SNPs regulate adipose tissue PPARg binding, function, and response to TZDs. In sum, we identified PPARg as an important transcription factor in adipocytes, and have uncovered its mechanisms of action at the genome.
Resistin. In 2001, we discovered the polypeptide hormone resistin as an adipocyte-specific, secreted protein whose gene expression was down-regulated by TZD treatment. We also discovered a family of other Resistin-Like Molecules (RELMs). We showed ectopic resistin exacerbated insulin resistance while genetic deletion of resistin improved glucose metabolism. We found that resistin expression in adipocytes requires a PPARg binding site that is present in the mouse genome but absent in humans (e), where resistin is secreted mainly from monocytes in response to inflammatory stimuli. Humanizing mice for resistin exacerbated insulin resistance due to inflammation. In sum, our discovery of resistin and its role in insulin resistance have contributed in a major way to current understanding of how adipokines and inflammation impact metabolism.
Transcriptional Regulation of Circadian Rhythms and Metabolism. Rev-erba is expressed with a large amplitude circadian rhythm in most cells and represses the activating clock gene BMAL1 via NCoR/HDAC3. We discovered that Rev-erba protein activity is modulated by heme ligand as well as by proteasomal degradation facilitated by lithium. We demonstrated that Rev-erba binds to the genome rhythmically with NCoR/HDAC3 leading to circadian modulation of the epigenome on a genome-wide scale and that loss of Rev-erbs a and b abolishes circadian rhythms. We also were first to characterize circadian enhancers in liver, and discovered the mechanism whereby Rev-erbs and other factors control multiple distinct phases of circadian gene expression. Genetic loss of the Rev-erbs, NCoR, or HDAC3 leads to massive hepatosteatosis in large part via a non-enzymatic function of HDAC3. We are currently interrogating the enzyme-independent functions of HDAC3 in liver. In brown adipose tissue, we discovered that Rev-erba controls circadian rhythm of cold tolerance and heat generation. Together, our studies have demonstrated circadian modulation of the epigenome and its relation to metabolism in health and disease.
FIRST NAME: | LAST NAME: | TITLE: | EMAIL: |
---|---|---|---|
Mitchell | Lazar | PI | lazar@pennmedicine.upenn.edu |
Brianna | Krusen | Research Specialist | Specialist/Brianna.Krusen@pennmedicine.upenn.edu |
Mindy | Kim | Research Specialst | mindy.kim2@pennmedicine.upenn.edu |
Trang | Trinh | Research Specialist | Trang.Trinh@pennmedicine.upenn.edu |
Lauren | Woodie | Post Doc | Lauren.Woodie@pennmedicine.upenn.edu |
Nagaswaroop | Nagaraj | Research Specialist | swaroop26oct@gmail.com |
Yuxia | Guan | Research | Specialist/Yuxia.Guan@pennmedicine.upenn.edu |
Bryce | Carpenter | Research Specialist | Specialist/Bryce.Carpenter@pennmedicine.upenn.edu |
Delaine Zayas-Bazan | Burgos | Grad Student | zde@pennmedicine.upenn.edu |
Kun | Zhu | Kun.Zhu@pennmedicine.upenn.edu |