Genomes and Genes
NUCLEAR HORMONE RECEPTORS IN ADIPOCYTE DIFFERENTIATION
Principal Investigator: Mitchell A Lazar
Abstract: DESCRIPTION (provided by applicant): A major goal of this laboratory is to understand the molecular mechanisms by which the nuclear hormone receptor peroxisome proliferator-activated receptor ? (PPAR?) controls adipogenesis and mediates antidiabetic effects of thiazolidinedione (TZD) drugs that improve insulin sensitivity but cause unwanted side effects. We hypothesize that target gene- and tissue- selective modulation of gene expression by PPAR? are dictated by different modes of PPAR? binding and synergy between PPAR? and cooperating transcription factors. Specific Aim 1 is to determine the direct transcriptional effect of TZDs in adipocytes and their relation to PPAR? binding on a genome-wide scale. We hypothesize that the direct effects of TZDs on transcription cannot be predicted from transcriptomic analysis. Preliminary Global Run-On sequencing (GRO-seq) results demonstrate the feasibility of measuring nascent transcripts in adipocytes on a genome-wide scale. Specific Aim 2 is to delineate the adipocyte epigenome and corepressor cistromes, and their relation to PPAR? binding and the effects of TZD treatment on a genome-wide scale. We hypothesize that TZD treatment of adipocytes alters coregulator recruitment to PPAR? at a subset of target genes, leading to epigenomic changes that alter gene transcription. This will be tested by ChIP-seq for coregulators and epigenomic marks in adipocytes treated with TZDs and non-TZD ligands with potentially fewer side effects. Specific Aim 3 is to understand the mechanisms of cell-type specific genomic binding and regulation by PPAR?. We hypothesize that PPAR? functions as a pioneer factor on some binding sites, particularly in adipocytes, whereas macrophage binding sites are more influenced by cell- specific transcription factors and epigenomic marks. This will be tested using cistromic approaches, and the ability of PPAR? and cell type-specific factors such as PU.1 to shape each other's genomic binding, as well as the adipocyte and macrophage epigenomes, will be explored using gain and loss of function studies. Our innovative approach will elucidate mechanisms underlying target gene- and tissue-specificity of PPAR?, which can be translated to the design of more selective insulin sensitizers to combat the epidemic of metabolic disorders.
Funding Period: 1995-07-01 - 2017-05-31
more information: NIH RePORT
- CXCL16 is a marker of inflammation, atherosclerosis, and acute coronary syndromes in humansMichael Lehrke
Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
J Am Coll Cardiol 49:442-9. 2007..This study was designed to determine the association of CXCL16 with inflammation, atherosclerosis, and acute coronary syndromes...
- Species-specific strategies underlying conserved functions of metabolic transcription factorsRaymond E Soccio
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6149, USA
Mol Endocrinol 25:694-706. 2011..Analysis of factor binding in multiple species may be necessary to distinguish apparent species-unique noise and reveal functionally relevant information...
- Repressor transcription factor 7-like 1 promotes adipogenic competency in precursor cellsAna G Cristancho
Division of Endocrinology, Department of Medicine and Genetics and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Proc Natl Acad Sci U S A 108:16271-6. 2011..These results establish TCF7L1 as a transcriptional hub coordinating cell-cell contact with the transcriptional repression required for adipogenic competency...
- Forming functional fat: a growing understanding of adipocyte differentiationAna G Cristancho
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, The Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Nat Rev Mol Cell Biol 12:722-34. 2011..Improving our understanding of these mechanisms may allow us to identify therapeutic targets against metabolic diseases that are rapidly becoming epidemic globally...
- Cell-specific integration of nuclear receptor function at the genomeLogan J Everett
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Wiley Interdiscip Rev Syst Biol Med 5:615-29. 2013..Emerging genomic technologies such as ChIP-seq and GRO-seq provide insights on a larger scale leading to deeper understanding of the complexities of transcriptional regulation by NRs...
- Pruning of the adipocyte peroxisome proliferator-activated receptor γ cistrome by hematopoietic master regulator PU.1Joanna R DiSpirito
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
Mol Cell Biol 33:3354-64. 2013..Together, these data reveal unexpected lability within the adipocyte PPARγ cistrome and show that, even in terminally differentiated cells, PU.1 can remodel the cistrome of another master regulator. ..
- The orphan nuclear receptors at their 25-year reunionShannon E Mullican
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
J Mol Endocrinol 51:T115-40. 2013..Here we provide a compendium of these so-called orphan receptors and focus on what has been learned about their modes of action, physiological functions, and therapeutic promise. ..
- Lipoatrophy and severe metabolic disturbance in mice with fat-specific deletion of PPARγFenfen Wang
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104
Proc Natl Acad Sci U S A 110:18656-61. 2013..Together, our data reveal the necessity of fat PPARγ in adipose formation, whole-body metabolic homeostasis, and normal development of fat-containing tissues. ..
- Metabolite and transcriptome analysis during fasting suggest a role for the p53-Ddit4 axis in major metabolic tissuesMichael Schupp
Institute for Genomics and Bioinformatics, Graz University of Technology, Petersgasse 14, Graz 8010, Austria
BMC Genomics 14:758. 2013..Because there is a lack of standardization for this procedure, we need a deeper understanding of the dynamics and the molecular mechanisms in fasting...
- Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancersSonia E Step
Division of Endocrinology, Diabetes, and Metabolism
Genes Dev 28:1018-28. 2014..Thus, rosi activates and represses transcription by fundamentally different mechanisms that could inform the future development of anti-diabetic drugs. ..
- Autoimmune kidney disease and impaired engulfment of apoptotic cells in mice with macrophage peroxisome proliferator-activated receptor gamma or retinoid X receptor alpha deficiencyTamas Roszer
Departamento de Cardiología Regenerativa, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain
J Immunol 186:621-31. 2011..These results demonstrate that stimulation of PPARγ and RXRα in macrophages facilitates apoptotic cell engulfment, and they provide a potential strategy to avoid autoimmunity against dying cells and to attenuate SLE...
- Endogenous ligands for nuclear receptors: digging deeperMichael Schupp
Department of Endocrinology, Diabetes, and Nutrition and Center for Cardiovascular Research, Institute of Pharmacology, Charite University Medicine Berlin, 10115 Berlin, Germany
J Biol Chem 285:40409-15. 2010..This knowledge about the nature and physiology of these ligands may create new opportunities for therapeutic drug development...
- PPARgamma regulates adipose triglyceride lipase in adipocytes in vitro and in vivoErin E Kershaw
Div of Endocrinology and Metabolism, Dept of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215, USA
Am J Physiol Endocrinol Metab 293:E1736-45. 2007..Thus, PPARgamma positively regulates ATGL mRNA and protein expression in mature adipocytes in vitro and in adipose tissue in vivo, suggesting a role for ATGL in mediating PPARgamma's effects on lipid metabolism...
- Resistin- and Obesity-associated metabolic diseasesM A Lazar
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and The Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6149, USA
Horm Metab Res 39:710-6. 2007..Given the emerging interrelationship between inflammation and metabolic disease, hyperresistinemia may be a biomarker, and/or a mediator, of metabolic and inflammatory diseases in humans as well as in rodents...
- Stereospecificity of retinol saturase: absolute configuration, synthesis, and biological evaluation of dihydroretinoidsAlexander R Moise
Department of Pharmacology, Case School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106 4965, USA
J Am Chem Soc 130:1154-5. 2008
- DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cellsDavid J Steger
Division of Hematology, Abramson Research Center 315A, The Children s Hospital of Philadelphia, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA
Mol Cell Biol 28:2825-39. 2008....
- Re-expression of GATA2 cooperates with peroxisome proliferator-activated receptor-gamma depletion to revert the adipocyte phenotypeMichael Schupp
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Univ of Pennsylvania School of Medicine, 700 CRB, 415 Curie Blvd, Philadelphia, PA 19104 6149, USA
J Biol Chem 284:9458-64. 2009..These results suggest that PPARgamma-independent down-regulation of GATA2 prevents reversion of mature adipocytes after PPARgamma depletion...
- Retinol saturase promotes adipogenesis and is downregulated in obesityMichael Schupp
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
Proc Natl Acad Sci U S A 106:1105-10. 2009..Thus, RetSat plays an important role in the biology of adipocytes, where it favors normal differentiation, yet is reduced in the obese state. RetSat is thus a novel target for therapeutic intervention in metabolic disease...
- Cell-specific determinants of peroxisome proliferator-activated receptor gamma function in adipocytes and macrophagesMartina I Lefterova
University of Pennsylvania School of Medicine, 700 CRB, 415 Curie Blvd, Philadelphia, PA 19104 6149, USA
Mol Cell Biol 30:2078-89. 2010..Our data support the existence of an epigenomic hierarchy in which PPARgamma binding to cell-specific sites not marked by repressive marks opens chromatin and leads to local activation marks, including histone acetylation...
- Propagation of adipogenic signals through an epigenomic transition stateDavid J Steger
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Genes Dev 24:1035-44. 2010..Thus, the conversion of preadipocyte to adipocyte involves the formation of an epigenomic transition state that is not observed in cells at the beginning or end of the differentiation process...
- PPARγ and the global map of adipogenesis and beyondMartina I Lefterova
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Trends Endocrinol Metab 25:293-302. 2014..These emerging considerations inform our understanding of PPARγ function as well as of adipocyte development and physiology. ..
- An integrative approach to construct a regulatory network effected by TDZsKyoung Jae Won; Fiscal Year: 2013....
- Transcriptional and epigenomic control of adipose tissue development and functionDavid J Steger; Fiscal Year: 2013....
- Role of NCoR in Adipose TissueMaryam Ahmadian; Fiscal Year: 2013..abstract_text> ..
- Circadian Repressors Cry1 and Cry2 Modulate Nuclear Hormone Receptor FunctionKatja A Lamia; Fiscal Year: 2013..This project involves the study of a novel regulator for nuclear hormone receptor function and will contribute to the knowledge base needed for the development of therapeutic strategies to treat metabolic disease. ..
- Transcriptional role of TLE3 in brown adipose tissue development and metabolismClaudio J Villanueva; Fiscal Year: 2013..The proposed studies are a logical transition from my postdoctoral studies in adipogenesis to the burgeoning field of brown adipocyte biology. ..
- Epigenetics of Obesity and Insulin ResistanceJane Kim; Fiscal Year: 2013..Jerrold Olefsky. This approach is designed to draw on my strengths as a bench scientist and pediatric endocrinologist, providing an independent focus of research and platform for future R01 funding. ..
- DIABETES AND ENDOCRINOLOGY RESEARCH CENTERDomenico Accili; Fiscal Year: 2013....
- OBESITY, ADIPOGENESIS, AND LIPID LIGANDSClay F Semenkovich; Fiscal Year: 2013..Identifying novel pathways for altering the function of fat cells has the potential to improve the metabolic milieu of obesity and treat obesity-associated diseases. ..
- EARLY EVENTS IN ALZHEIMER PATHOGENESISSUE TILTON GRIFFIN; Fiscal Year: 2013..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
- Inflammatory responses of vascular cellsPaul L Fox; Fiscal Year: 2013..abstract_text> ..
- HORMONAL REGULATION OF MAMMALIAN GENE EXPRESSIONRonald M Evans; Fiscal Year: 2013....
- Connection of Mineral and Energy Metabolism by the Nuclear Receptor PPAR-gammaYihong Wan; Fiscal Year: 2013..Therefore, this investigation will significantly impact the broader scientific, clinical, and patient community. ..
- Translating human PPARy binding regions to gene regulation and metabolic diseaseRAYMOND EDWARD SOCCIO; Fiscal Year: 2013..Soccio from the mentored to the independent phase of this 5 year career development award. These studies of the human PPAR cistrome have potentially great translational relevance to the epidemics of diabetes and obesity. . ..
- Regulatory Mechanisms In Intestinal MotilityKenton M Sanders; Fiscal Year: 2013..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..
- Gene Networks controlling macrophage-adipocyte interactions in insulinChristopher K Glass; Fiscal Year: 2013..abstract_text> ..
- The Center for Native and Pacific Health Disparities ResearchMARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..