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Transcriptional regulation of the human growth hormone receptor (hGHR) gene V2 promoter by transcriptional activators and repressor.

ABSTRACT: The V2 transcript is the major ubiquitously expressed human GH receptor (hGHR) mRNA in all tissues examined to date. In a previous investigation, we defined the V2 promoter as TATA-less and exhibiting many characteristics of a housekeeping gene promoter. We also demonstrated that its basal activity is determined by several different cis-regulatory regions within both the promoter and the V2 exon. In the present study, we used luciferase-reporter, site-directed mutagenesis, gel shift, chromatin immunoprecipitation, and quantitative RT-PCR assays to investigate the ability of certain transcription factors to regulate hGHR V2 transcription through these regions in mammalian cells, including human adipocytes. Ets1 was found to transactivate the V2 proximal promoter through specific Ets sites. Two CCAAT/enhancer-binding protein (C/EBP) family members [C/EBP-homologous protein (CHOP) and C/EBPbeta] enhanced V2 transcription via different pathways: indirectly, by association with a V2 exon region (CHOP), and directly, using a V2 proximal promoter noncanonical binding site (C/EBPbeta). The Notch signaling mediator, Hes1, potently suppressed V2 promoter activity through interaction with two Hes sites within the V2 exon. We propose that these transcriptional factors regulate hGHR V2 expression by acting as downstream nuclear effectors, linking specific signaling cascades (e.g. MAPK and Notch) triggered by different growth factor-, development-, and nutrition- as well as stress-related stimuli. Our data also suggest that these factors are likely to be important in the differentiation-induced increase in V2 mRNA expression in adipocytes, with Ets1 and CHOP functioning at the preadipocyte stage to prepare the cells for differentiation and increasing C/EBPs and decreasing Hes1 levels contributing during adipocyte maturation.

SUBMITTER: Wei Y

PROVIDER: S-EPMC5428159 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Transcriptional regulation of the human growth hormone receptor (hGHR) gene V2 promoter by transcriptional activators and repressor.

Wei Yuhong Y Puzhko Svetlana S Wabitsch Martin M Goodyer Cynthia Gates CG

Molecular endocrinology (Baltimore, Md.) 20081230 3

The V2 transcript is the major ubiquitously expressed human GH receptor (hGHR) mRNA in all tissues examined to date. In a previous investigation, we defined the V2 promoter as TATA-less and exhibiting many characteristics of a housekeeping gene promoter. We also demonstrated that its basal activity is determined by several different cis-regulatory regions within both the promoter and the V2 exon. In the present study, we used luciferase-reporter, site-directed mutagenesis, gel shift, chromatin i ...[more]

PMID: 19116245

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Project description:Long intergenic noncoding RNAs (lincRNAs) are increasingly recognized as key chromatin regulators, yet few studies have characterized lincRNAs in a single tissue under diverse conditions. Here, we analyzed 45 mouse liver RNA sequencing (RNA-Seq) data sets collected under diverse conditions to systematically characterize 4,961 liver lincRNAs, 59% of them novel, with regard to gene structures, species conservation, chromatin accessibility, transcription factor binding, and epigenetic states. To investigate the potential for functionality, we focused on the responses of the liver lincRNAs to growth hormone stimulation, which imparts clinically relevant sex differences to hepatic metabolism and liver disease susceptibility. Sex-biased expression characterized 247 liver lincRNAs, with many being nuclear RNA enriched and regulated by growth hormone. The sex-biased lincRNA genes are enriched for nearby and correspondingly sex-biased accessible chromatin regions, as well as sex-biased binding sites for growth hormone-regulated transcriptional activators (STAT5, hepatocyte nuclear factor 6 [HNF6], FOXA1, and FOXA2) and transcriptional repressors (CUX2 and BCL6). Repression of female-specific lincRNAs in male liver, but not that of male-specific lincRNAs in female liver, was associated with enrichment of H3K27me3-associated inactive states and poised (bivalent) enhancer states. Strikingly, we found that liver-specific lincRNA gene promoters are more highly species conserved and have a significantly higher frequency of proximal binding by liver transcription factors than liver-specific protein-coding gene promoters. Orthologs for many liver lincRNAs were identified in one or more supraprimates, including two rat lincRNAs showing the same growth hormone-regulated, sex-biased expression as their mouse counterparts. This integrative analysis of liver lincRNA chromatin states, transcription factor occupancy, and growth hormone regulation provides novel insights into the expression of sex-specific lincRNAs and their potential for regulation of sex differences in liver physiology and disease.

Dataset Information

Transcriptional regulation of the human growth hormone receptor (hGHR) gene V2 promoter by transcriptional activators and repressor.

Publications

Transcriptional regulation of the human growth hormone receptor (hGHR) gene V2 promoter by transcriptional activators and repressor.

Similar Datasets

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