title: The effects of PPARγ on the regulation of the TOMM40-APOE-C1 genes cluster.
abstract: Chromosome 19q13.32 is a gene rich region, and has been implicated in multiple human phenotypes in adulthood including lipids traits, Alzheimer's disease, and longevity. Peroxisome Proliferator Activated Receptor Gamma (PPARγ) is a ligand-activated nuclear transcription factor that plays a role in human complex traits that are also genetically associated with the chromosome 19q13.32 region. Here, we study the effects of PPARγ on the regional expression regulation of the genes clustered within chromosome 19q13.32, specifically TOMM40, APOE, and APOC1, applying two complementary approaches. Using the short hairpin RNA (shRNA) method in the HepG2 cell-line we knocked down PPARγ expression and measured the effect on mRNA expression. We discovered PPARγ knock down increased the levels of TOMM40-, APOE-, and APOC1-mRNAs, with the highest increase in expression observed for APOE-mRNA. To complement the PPARγ knockdown findings we also examined the effects of low doses of PPARγ agonists (nM range) on mRNA expression of these genes. Low (nM) concentrations of pioglitazone (Pio) decreased transcription of TOMM40, APOE, and APOC1 genes, with the lowest mRNA levels for each gene observed at 1.5nM. Similar to the effect of PPARγ knockdown, the strongest response to pioglitazone was also observed for APOE-mRNA, and rosiglitazone (Rosi), another PPARγ agonist, produced results that were consistent with these. In conclusion, our results further established a role for PPARγ in regional transcriptional regulation of chr19q13.32, underpinning the association between PPARγ, the chr19q13.32 genes cluster, and human complex traits and disease.
authors.affiliation: Department of Neurology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Shobana
authors.initials: S
authors.lastname: Subramanian
authors.affiliation: Department of Neurology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: William K
authors.initials: WK
authors.lastname: Gottschalk
authors.affiliation: Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: So Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Neurology, Duke University Medical Center, Durham, NC 27710, USA; Zinfandel Pharmaceuticals, Chapel Hill, NC, USA.
authors.forename: Allen D
authors.initials: AD
authors.lastname: Roses
authors.affiliation: Department of Neurology, Duke University Medical Center, Durham, NC 27710, USA; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: o.chibafalek@duke.edu.
authors.forename: Ornit
authors.initials: O
authors.lastname: Chiba-Falek
mesh_terms: D053302:Apolipoprotein C-I / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D005810:Multigene Family; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics
chemical_list: C505803:APOC1 protein, human; D053302:Apolipoprotein C-I; D001057:Apolipoproteins E; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D047495:PPAR gamma; D012333:RNA, Messenger; C400783:TOMM40 protein, human
keywords: APOC1; APOE; Chromosome 19q13.32; PPARγ; TOMM40; Transcription