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Title: Regulation of gene expression by the nuclear receptor corepressor RIP140 in adipocytes
Author: Kiskinis, Evangelos
ISNI:       0000 0001 3816 2011
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2008
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Nuclear receptors (NR) are ligand-induced transcription factors that regulate the expression of genes involved in a number of physiological processes including metabolism. Their ability to regulate transcription is dependent on the recruitment of specific cofactors that remodel chromatin and promote the assembly of the basal transcriptional machinery. Receptor interacting protein 140 (RIP140) is a corepressor for NRs that utilizes four independent repression domains to inhibit gene expression of target genes. While RIP140-null mice develop around 70% less white adipose tissue than wild-type littermates, the process of adipogenesis is unaffected in RIP140-null and RIP140-expressing cells. To elucidate the intrinsic role of RIP140 in adipocytes I used full mouse genome arrays to compare the gene expression profiles of pre-adipocytes and adipocytes with and without RIP140. I demonstrate that the transcriptional corepressor negatively regulates major gene clusters in a number of metabolic pathways including glycolysis, TCA cycle, oxidative phosphorylation, fatty acid oxidation and glycerol metabolism. Additionally, a futile metabolic cycle of triglyceride recycling is activated in RIP140 null adipocytes. In order to determine the molecular mechanism of RIP140 repression I analysed the epigenetic profile of Ucp1, a gene which is typically expressed in brown but not white adipocytes. I utilized RIP140-null and RIP140-expressing adipocytes and found that RIP140 is essential for both DNA and histone methylation to maintain gene repression. RIP140 expression promotes the assembly of DNA and histone methyltransferases on the Ucp1 enhancer and leads to methylation of specific CpG residues and histones as judged by bisulphite genomic sequencing and chromatin immunoprecipitation assays. These results suggest that RIP140 serves as a scaffold for both DNA and histone methyltransferase activities to inhibit gene transcription by two key epigenetic repression systems. RIP140 could potentially act to divert white adipocytes from a brown fat phenotype by repressing genes involved in fatty acid oxidation and mitochondrial respiration and by silencing genes like Ucp1.
Supervisor: Parker, Malcolm Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral