Regulation of adipocyte transcription by PPARgamma ligands.

Format:

Book

Thesis/Dissertation

Author/Creator:

Step, Sonia E, author.

Contributor:

Lazar, Mitchell A., degree supervisor.

University of Pennsylvania. Pharmacology.

Language:

English

Subjects (All):

Molecular biology.

Genetics.

Pharmacology--Penn dissertations.

Penn dissertations--Pharmacology.

Local Subjects:

Molecular biology.

Genetics.

Pharmacology--Penn dissertations.

Penn dissertations--Pharmacology.

Genre:

Academic theses.

Physical Description:

1 online resource (122 pages)

Contained In:

Dissertation Abstracts International 76-05B(E).

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor, MI : ProQuest, 2014.

System Details:

Mode of access: World Wide Web.

text file

Summary:

Rosiglitazone (rosi) is a powerful insulin sensitizer, but serious toxicities have curtailed its widespread clinical use. Rosi functions as a high-affinity ligand for PPARgamma, the adipocyte-predominant nuclear receptor (NR). The classic model of NR action, involving binding of ligand to the NR on DNA, explains positive regulation of gene expression, but both ligand-dependent transcriptional repression and indirect regulation are not well understood. We have addressed these issues by studying the direct effects of rosiglitazone on gene transcription, using global run-on sequencing (GRO-seq). Rosi-induced changes in gene body transcription were pronounced after 10 minutes and correlated with steady-state mRNA levels as well as with transcription at nearby enhancers (eRNAs). Up-regulated eRNAs occurred almost exclusively at PPARgamma binding sites, to which rosi treatment recruited coactivators including MED1, p300, and CBP, without changes in binding of the corepressor NCoR. By contrast, down-regulated eRNAs fell in sites devoid of PPARgamma but enriched for a variety of other TFs in the C/EBP and AP-1 families. These enhancers lost coactivator binding upon rosi treatment, suggesting that rosi treatment causes redistribution of coactivators to PPARgamma sites and away from enhancers containing other TFs, leading to transcriptional repression at these eRNAs and their target genes. We also investigated the function of MRL-24, a compound that has been shown to lack PPARgamma transactivation activity and regulate a distinct subset of PPARgamma target genes while functioning as an equally effective insulin sensitizer as rosi. Though our goal was to identify whether MRL-24 regulates the same functional enhancers marked by eRNAs as rosi, we instead found that MRL-24 does not control a distinct subset of target genes, but rather acts as a partial agonist for PPARgamma. Together, these studies further our understanding of transcriptional regulation by modulation of PPARgamma activity, including insights into determining functional enhancers and mechanisms of transcriptional repression by activation of a NR.

Notes:

Source: Dissertation Abstracts International, Volume: 76-05(E), Section: B.

Adviser: Mitchell A. Lazar.

Department: Pharmacology.

Thesis Ph.D. University of Pennsylvania 2014.

Local Notes:

School code: 0175.

ISBN:

9781321480221

Access Restriction:

Restricted for use by site license.