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Principal Investigator: Yu-Hua Tseng
Organization: JOSLIN DIABETES CENTER
Fiscal Year: 2023
Award: $623,366
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary/Abstract
Obesity and its metabolic sequelae are rapidly increasing in the United States and worldwide, leading to high
morbidity and mortality in type 2 diabetes, cardiovascular disease, and certain cancer. Under the current
pandemic, obesity has been recognized as a key risk factor for severe COVID-19. Central to these pathologies
is adipose tissue. There are functionally distinct types of adipose tissue. White adipose tissue is the primary
site of the triglyceride storehouse. In contrast, thermogenic fat, which consists of classical brown adipose
tissue (BAT) and inducible beige/brite adipocytes, concentrates on thermogenic energy expenditure. It has
been recently reported that people with BAT have a significantly lower prevalence of cardiometabolic diseases,
highlighting the metabolic benefits and therapeutic potential of BAT in humans. To make the therapeutics
possible, improved knowledge of the regulation of thermogenic adipocytes is urgently needed. The
thermogenic function of brown and beige adipocytes are coordinately regulated by specific transcriptional and
epigenetic regulators. While transcription of the thermogenic gene uncoupling protein 1 (Ucp1) in response to
beta-adrenergic stimulation has been broadly studied, little is known about how histone positioning and
chromatin folding influences the expression of Ucp1 and other thermogenic genes. Using an unbiased
CRISPR-based screen, we identified the histone variant H2A.Z and the LIM domaining-containing zinc-finger
protein Crip2 as trans-acting factors recruited to the Ucp1 promoter/enhancer region by beta3-adrenergic
receptor stimulation. Importantly, deletion of H2A.Z or Crip2 in mature brown adipocytes not only impeded
Ucp1 transcription, but also reduced the expression of multiple thermogenic genes and led to impaired cellular
thermogenesis. This proposal will determine the signaling events mediating the activation of Crip2 and H2A.Z
deposition and the impact of Crip2 or H2A.Z deficiency in the cellular thermogenesis and bioenergetic profiles
of thermogenic adipocytes murine and human origins. Since histone variants play an important role in
determining chromatin remodeling, we will examine how Crip2-H2A.Z interaction influences chromatin
architecture, thereby regulating thermogenic transcription and cellular respiration. To establish the
physiological significance of Crip2 and H2A.Z in metabolic regulation, we will generate brown fat-specific Crip2
or H2A.Z knockout mice and thoroughly characterize their metabolic phenotypes. Completing the proposed
studies will increase fundamental knowledge on the role of chromatin remodeling in the regulation of
thermogenic program and pave ways to establish new therapeutic approaches for combating metabolic
diseases.
Terms: <3'5'-cyclic ester of AMP><3-D><3-Dimensional><3D><ATAC sequencing><ATAC-seq><ATACseq><ATP Synthesis><ATP Synthesis Pathway><Ablation><Achievement><Achievement Attainment><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine Cyclic Monophosphate-Dependent Protein Kinases><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Adipocytes><Adipose Cell><Adipose tissue><Adrenergic Agents><Adrenergic Drugs><Adrenergic Receptor><Adrenergics><Adrenoceptors><Adult-Onset Diabetes Mellitus><Affect><Architecture><Area><BAT uncoupling protein><Basal Transcription Factor><Basal transcription factor genes><Binding><Bio-Informatics><Bioenergetics><Bioinformatics><Biology><Brown Adipose Tissue><Brown Fat><CRISPR approach><CRISPR based approach><CRISPR editing screen><CRISPR method><CRISPR methodology><CRISPR screen><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based screen><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 screen><CRISPR/Cas9 technology><CRR Domain><CSAID-Binding Protein 1><CSAID-Binding Protein 2><CSBP2><Cancers><Cardiometabolic Disease><Cardiometabolic Disorder><Cardiovascular Diseases><Cas nuclease technology><Cell Aging><Cell Body><Cell Communication and Signaling><Cell Nucleus><Cell Respiration><Cell Senescence><Cell Signaling><Cells><Cellular Aging><Cellular Respiration><Cellular Senescence><ChIP Sequencing><ChIP-seq><ChIPseq><Chromatin><Chromatin Loop><Chromatin Loop Domains><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Complex><Cyclic AMP><Cyclic AMP-Dependent Protein Kinases><Cysteine Rich Region><Cytokine-Suppressive Antiinflammatory Drug-Binding Protein 1><Cytokine-Suppressive Antiinflammatory Drug-Binding protein 2><DNA Loop><DNA-Dependent RNA Polymerase II><Data><Deposit><Deposition><Distal><Elements><Energy Expenditure><Energy Metabolism><Engineering / Architecture><Enhancers><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epinephrine Receptors><Event><Extracellular Signal-Regulated Kinase Gene><Fat Cells><Fats><Fatty Tissue><Fatty acid glycerol esters><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Transcription><Genome Mappings><Genomics><Heat Production><Hibernating Gland><Histones><Human><Impairment><Intermediary Metabolism><Intracellular Communication and Signaling><KO mice><Ketosis-Resistant Diabetes Mellitus><Knock-out Mice><Knockout Mice><Knowledge><LIM Domain><Lipocytes><Low Prevalence><MAP Kinase Gene><MAPK><MAPK14><MAPK14 Mitogen-Activated Protein Kinase><MAPK14 gene><Malignant Neoplasms><Malignant Tumor><Maps><Mature Lipocyte><Mature fat cell><Maturity-Onset Diabetes Mellitus><Mediating><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Processes><Metabolism><Mice><Mice Mammals><Mitogen-Activated Protein Kinase 14><Mitogen-Activated Protein Kinase Gene><Modeling><Modern Man><Molecular><Molecular Interaction><Morbidity><Morbidity - disease rate><Murine><Mus><Mxi2><NIDDM><Nature><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Non-Polyadenylated RNA><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nuclear Translocation><Nucleus><Null Mouse><Obesity><Organism-Level Process><Organismal Process><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><PKA><Pancreatic beta Cell><Pancreatic β-Cell><Pathology><Persons><Phosphorylation><Phosphorylation Site><Physiologic><Physiologic Processes><Physiological><Physiological Processes><Play><Position><Positioning Attribute><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Process><Promoter Regions><Promotor Regions><Protein Kinase A><Protein Modification><Protein Phosphorylation><Proteins><RNA><RNA Expression><RNA Gene Products><RNA Polymerase B><RNA Polymerase II><RNA Seq><RNA sequencing><RNAseq><Receptor Signaling><Regulation><Replicative Senescence><Reporting><Resolution><Ribonucleic Acid><Risk Factors><Rodent><Rodentia><Rodents Mammals><Role><SAPK2A><Scheme><Signal Induction><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><Site-Directed Mutagenesis><Site-Specific Mutagenesis><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Stress-Activated Protein Kinase 2A><Structure of beta Cell of islet><System><T2 DM><T2D><T2DM><Targeted DNA Modification><Targeted Modification><Techniques><Testing><Therapeutic><Thermogenesis><Thesaurismosis><Trans-Acting Factors><Trans-Activators><Transactivators><Transcription><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><Triacylglycerol><Triglycerides><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><United States><Variant><Variation><Zinc Finger Domain><Zinc Finger Motifs><Zinc Fingers><adenoreceptor><adenosine 3'5' monophosphate><adipose><adiposity><adult onset diabetes><aerobic metabolism><aerobic respiration><biological signal transduction><brown adipose tissue uncoupling protein><cAMP><cAMP-Dependent Protein Kinases><cardiovascular disorder><cell type><chromatin immunoprecipitation-sequencing><chromatin remodeling><clustered regularly interspaced short palindromic repeats screen><comparative><computational tools><computerized tools><corpulence><current pandemic><epigenetic regulation><epigenetically><genetic promoter element><genetic promoter sequence><genome scale><genome-wide><genomewide><genomic data><genomic data-set><genomic dataset><improved><in vivo><islet><ketosis resistant diabetes><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><mRNA Expression><malignancy><maturity onset diabetes><metabolic phenotype><metabolism disorder><metabotype><mortality><neoplasm/cancer><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><overexpress><overexpression><oxidative metabolism><p38><p38 MAP Kinase><p38 MAPK Gene><p38 Mitogen Activated Protein Kinase><p38 Protein Kinase><p38 SAPK><p38-Alpha><p38Alpha><pancreas beta cell><pancreas β cell><pancreatic b-cell><phospho-proteomics><phosphoproteomics><present pandemic><prevent><preventing><programs><promoter><promoter sequence><promotor><protein expression><recruit><resolutions><response><senescence><senescent><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><social role><therapeutic target><thermogenin><three dimensional><transcription factor><transcriptome sequencing><transcriptomic sequencing><type 2 DM><type II DM><type two diabetes><uncoupling protein 1><white adipose tissue><yellow adipose tissue>