Nuclear """"""""orphan"""""""" receptors are members of the thyroid/steroid hormone receptor superfamily of transcription factors whose ligand-specificity, if any, is unknown. Rev-ErbAalpha is a fascinating orphan receptor whose gene expression may regulate alternative splicing of the alpha thyroid hormone (T3) receptor and c-erbAalpha2, another orphan receptor which inhibits T3 action, whose gene overlaps that of Rev-ErbAalpha but is transcribed from the opposite strand. Interestingly, Rev-ErbAalpha gene expression is basally repressed by labile proteins and induced during adipocyte differentiation. This laboratory is interested in the regulation and regulatory role of Rev-ErbAalpha gene expression, as well as in the function of the Rev-ErbAalpha protein, which is completely unknown at present.
The specific aims of this proposal are to: (1) study the regulation of Rev-ErbAalpha expression at the gene and protein levels, (2) determine the functional significance of the Rev-ErbAalpha/c-erbAalpha2 genomic relationship in light of the demonstrated ability of Rev-ErbAalpha to interfere with splicing in vitro, and (3) characterize the DNA-binding and transcriptional properties of Rev-ErbAalpha protein. The Rev-ErbAalpha gene promoter will be isolated and characterized, and transcription factors which regulate Rev-ErbAalpha expression by binding to these sequences will be cloned. Rev-ErbAalpha antisera will be used to demonstrate Rev- ErbAalpha protein expression, correlate mRNA and protei levels, and study post-translational modification of Rev-ErbAalpha. Also, the ability of Rev-ErbAalpha transcripts to inhibit the splicing of endogenous and cotransfected c-erbAalpha2 will be evaluated to determine whether this novel regulatory mechanism functions in vivo. In addition, the function of the Rev-ErbAalpha protein will be explored by amplifying, isolating, and sequencing its preferred DNA-binding sites. The specificity of DNA-binding by Rev-ErbAalpha will be compared with that of other nuclear receptors, and the ability of wild-type and chimeric forms of Rev-ErbAalpha to regulate gene transcription from reporter genes containing Rev-ErbAalpha binding sites will be evaluated. The long term goal of this work is to understand the role of this novel orphan receptor in cell growth and differentiation. These studies will also provide insight into the biological significance of orphan receptors as well as the mechanisms of action of nuclear hormone receptor family members.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK045586-01
Application #
3247068
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1992-09-30
Project End
1996-09-29
Budget Start
1992-09-30
Budget End
1993-09-29
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Emmett, Matthew J; Lazar, Mitchell A (2018) Integrative regulation of physiology by histone deacetylase 3. Nat Rev Mol Cell Biol :
Kim, Yong Hoon; Marhon, Sajid A; Zhang, Yuxiang et al. (2018) Rev-erb? dynamically modulates chromatin looping to control circadian gene transcription. Science 359:1274-1277
Guan, Dongyin; Xiong, Ying; Borck, Patricia C et al. (2018) Diet-Induced Circadian Enhancer Remodeling Synchronizes Opposing Hepatic Lipid Metabolic Processes. Cell 174:831-842.e12
Zhang, Yuxiang; Papazyan, Romeo; Damle, Manashree et al. (2017) The hepatic circadian clock fine-tunes the lipogenic response to feeding through ROR?/?. Genes Dev 31:1202-1211
Emmett, Matthew J; Lim, Hee-Woong; Jager, Jennifer et al. (2017) Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge. Nature 546:544-548
Lazar, Mitchell A (2017) Maturing of the nuclear receptor family. J Clin Invest 127:1123-1125
Jager, Jennifer; Wang, Fenfen; Fang, Bin et al. (2016) The Nuclear Receptor Rev-erb? Regulates Adipose Tissue-specific FGF21 Signaling. J Biol Chem 291:10867-75
Zhang, Yuxiang; Fang, Bin; Damle, Manashree et al. (2016) HNF6 and Rev-erb? integrate hepatic lipid metabolism by overlapping and distinct transcriptional mechanisms. Genes Dev 30:1636-44
Bass, Joseph; Lazar, Mitchell A (2016) Circadian time signatures of fitness and disease. Science 354:994-999

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