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Research resource: Genome-wide mapping of in vivo androgen receptor binding sites in mouse epididymis.

ABSTRACT: Epididymal function depends on androgen signaling through the androgen receptor (AR), although most of the direct AR target genes in epididymis remain unknown. Here we globally mapped the AR binding regions in mouse caput epididymis in which AR is highly expressed. Chromatin immunoprecipitation sequencing indicated that AR bound selectively to 19,377 DNA regions, the majority of which were intergenic and intronic. Motif analysis showed that 94% of the AR binding regions harbored consensus androgen response elements enriched with multiple binding motifs that included nuclear factor 1 and activator protein 2 sites consistent with combinatorial regulation. Unexpectedly, AR binding regions showed limited conservation across species, regardless of whether the metric for conservation was based on local sequence similarity or the presence of consensus androgen response elements. Further analysis suggested the AR target genes are involved in diverse biological themes that include lipid metabolism and sperm maturation. Potential novel mechanisms of AR regulation were revealed at individual genes such as cysteine-rich secretory protein 1. The composite studies provide new insights into AR regulation under physiological conditions and a global resource of AR binding sites in a normal androgen-responsive tissue.

SUBMITTER: Hu S

PROVIDER: S-EPMC2999474 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Research resource: Genome-wide mapping of in vivo androgen receptor binding sites in mouse epididymis.

Hu Shuanggang S Yao Guangxin G Guan Xiaojun X Ni Zimei Z Ma Wubin W Wilson Elizabeth M EM French Frank S FS Liu Qiang Q Zhang Yonglian Y

Molecular endocrinology (Baltimore, Md.) 20101013 12

Epididymal function depends on androgen signaling through the androgen receptor (AR), although most of the direct AR target genes in epididymis remain unknown. Here we globally mapped the AR binding regions in mouse caput epididymis in which AR is highly expressed. Chromatin immunoprecipitation sequencing indicated that AR bound selectively to 19,377 DNA regions, the majority of which were intergenic and intronic. Motif analysis showed that 94% of the AR binding regions harbored consensus androg ...[more]

PMID: 20943813

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Project description:The transformation of prostate cancer from an androgen-dependent state to an androgen-independent state is a lethal progression. Alterations in transcriptional programs are the basis of prostate cancer deterioration. The androgen receptor (AR), a member of the nuclear hormone receptor superfamily, mediates prostate cancer progression by functioning primarily through the ligand-activated transcription of target genes. Therefore, a detailed map of AR-regulated genes and AR genomic binding sites is required for hormone-naive and castration-resistant prostate cancer. Through the use of chromatin immunoprecipitation in combination with direct sequencing, 4,143 AR binding sites were defined in the LNCaP androgen-sensitive prostate cancer cell line. Using the same method, 2,380 AR binding regions were identified in the LNCaP-AI long-term androgen-deprived cell line. Approximately 8.5% (354/4,143) of the binding regions were mapped to within 2 kb of the transcription start site (TSS) in the LNCaP cells, while ?12.6% (299/2,380) were mapped to within 2 kb of the TSS in the LNCaP-AI cells. In total, the study mapped 2,796 genes in LNCaP cells and 1,854 genes in LNCaP-AI cells. The cell lines shared 789 mutual genes. In addition, gene ontology (GO) analysis of the genes revealed that there was a notable overlap between the GO terms in the LNCaP cells and LNCaP-AI cells. However, GO terms within the biological process domain that were only observed in the LNCaP-AI cells included the reproduction process, death, immune system process, multi-organism process, pigmentation and viral reproduction. The major genes in the different GO terms were TNFAIP8, RTN4, APP and SYNE1. Through analyzing the AR binding sites in the two cell types, the present study aimed to map potential AR-regulated genes, identify their associated transcription factors and provide a new perspective on the biological processes in the development of prostate cancer. The results provided a valuable data set that furthered the understanding of the genome-wide analysis of AR binding sites in prostate cancer cells, which may be exploited for the development of novel prostate cancer therapeutic strategies.

Project description:Hypoxia Inducible Factor (HIF) regulates a cascade of transcriptional events in response to decreased oxygenation, acting from the cellular to the physiological level. This response is evolutionarily conserved, allowing the use of zebrafish (Danio rerio) as a model for studying the hypoxic response. Activation of the hypoxic response can be achieved in zebrafish by homozygous null mutation of the von Hippel-Lindau (vhl) tumour suppressor gene. Previous work from our lab has focused on the phenotypic characterisation of this mutant, establishing the links between vhl mutation, the hypoxic response and cancer. To further develop fish as a model for studying hypoxic signalling, we examine the transcriptional profile of the vhl mutant with respect to Hif-1?. As our approach uses embryos consisting of many cell types, it has the potential to uncover additional HIF regulated genes that have escaped detection in analogous mammalian cell culture studies.We performed high-density oligonucleotide microarray analysis of the gene expression changes in von Hippel-Lindau mutant zebrafish, which identified up-regulation of well-known hypoxia response genes and down-regulation of genes primarily involved in lipid processing. To identify the dependency of these transcriptional changes on HIF, we undertook Chromatin Immunoprecipitation linked next generation sequencing (ChIP-seq) for the transcription factor Hypoxia Inducible Factor 1? (HIF-1?). We identified HIF-1? binding sites across the genome, with binding sites showing enrichment for an RCGTG motif, showing conservation with the mammalian hypoxia response element.Transcriptome analysis of vhl mutant embryos detected activation of key hypoxia response genes seen in human cell models of hypoxia, but also suppression of many genes primarily involved in lipid processing. ChIP-seq analysis of Hif-1? binding sites unveiled an unprecedented number of loci, with a high proportion containing a canonical hypoxia response element. Whether these sites are functional remains unknown, nevertheless their frequent location near transcriptional start sites suggests functionality, and will allow for investigation into the potential hypoxic regulation of genes in their vicinity. We expect that our data will be an excellent starting point for analysis of both fish and mammalian gene regulation by HIF.

Project description:BACKGROUND: Metastasis-associated protein 1 (MTA1), the founding member of the MTA family of genes, can modulate transcription by influencing the status of chromatin remodeling. Despite its strong correlation with the metastatic potential of cancer cells, MTA1 can also regulate crucial cellular pathways by modifying the acetylation status. We have previously reported the presence of MTA1/MTA1 in human and mouse testes, providing the evidence for its involvement in the regulation of testicular function during murine spermatogenesis. The objective of present study was to further assess the localization of MTA1 in mouse epididymis on both transcriptional and translational level, and then to explore whether MTA1 expression is regulated by androgens and postnatal epididymal development. METHODOLOGY/PRINCIPAL FINDINGS: Mice were deprived of circulating androgen by bilaterally castration and were then supplemented with exogenous testosterone propionate for one week. MTA1 was immunolocalized in the epithelium of the entire epididymis with the maximal expression in the nuclei of principal cells and of clear cells in proximal region. Its expression decreased gradually after castration, whereas testosterone treatment could restore the expression, indicating that the expression of this gene is dependent on androgen. During postnatal development, the protein expression in the epididymis began to appear from day 7 to day 14, increased dramatically from postnatal day 28, and peaked at adulthood onwards, coinciding with both the well differentiated status of epididymis and the mature levels of circulating androgens. This region- and cell-specific pattern was also conservative in normal human epididymis. CONCLUSIONS: Our data suggest that the expression of MTA1 protein could be regulated by androgen pathway and its expression level is closely associated with the postnatal development of the epididymis, giving rise to the possibility that this gene plays a potential role in sperm maturation and fertility.

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Research resource: Genome-wide mapping of in vivo androgen receptor binding sites in mouse epididymis.

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Research resource: Genome-wide mapping of in vivo androgen receptor binding sites in mouse epididymis.

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