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Integrated analysis identifies a class of androgen-responsive genes regulated by short combinatorial long-range mechanism facilitated by CTCF.

Taslim C, Chen Z, Huang K, Huang TH, Wang Q, Lin S - Nucleic Acids Res. (2012)

Bottom Line: In this study, we carried out an integrated analysis combining several types of high-throughput data, including genome-wide distribution data of H3K4 di-methylation (H3K4me2), CCCTC binding factor (CTCF), AR and FoxA1 cistrome data as well as androgen-regulated gene expression data.We found that a subset of androgen-responsive genes was significantly enriched near AR/H3K4me2 overlapping regions and FoxA1 binding sites within the same CTCF block.Our results suggest a relatively short combinatorial long-range regulation mechanism facilitated by CTCF blocking.

View Article: PubMed Central - PubMed

Affiliation: Department of Statistics, The Ohio State University, Columbus, OH 43210, USA.

ABSTRACT
Recently, much attention has been given to elucidate how long-range gene regulation comes into play and how histone modifications and distal transcription factor binding contribute toward this mechanism. Androgen receptor (AR), a key regulator of prostate cancer, has been shown to regulate its target genes via distal enhancers, leading to the hypothesis of global long-range gene regulation. However, despite numerous flows of newly generated data, the precise mechanism with respect to AR-mediated long-range gene regulation is still largely unknown. In this study, we carried out an integrated analysis combining several types of high-throughput data, including genome-wide distribution data of H3K4 di-methylation (H3K4me2), CCCTC binding factor (CTCF), AR and FoxA1 cistrome data as well as androgen-regulated gene expression data. We found that a subset of androgen-responsive genes was significantly enriched near AR/H3K4me2 overlapping regions and FoxA1 binding sites within the same CTCF block. Importantly, genes in this class were enriched in cancer-related pathways and were downregulated in clinical metastatic versus localized prostate cancer. Our results suggest a relatively short combinatorial long-range regulation mechanism facilitated by CTCF blocking. Under such a mechanism, H3K4me2, AR and FoxA1 within the same CTCF block combinatorially regulate a subset of distally located androgen-responsive genes involved in prostate carcinogenesis.

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Genes in Class 1 shows distinctive pattern in metastatic prostate cancer while Class 2 shows less distinctive markings. Color represents log2 ratios of expression. When the expression value is not available, it is denoted by gray color.
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gks139-F6: Genes in Class 1 shows distinctive pattern in metastatic prostate cancer while Class 2 shows less distinctive markings. Color represents log2 ratios of expression. When the expression value is not available, it is denoted by gray color.

Mentions: Finally, we evaluated the biological significance of the genes (focusing on Class 1) for prostate cancer progression. We assess the expression of these genes in the analysis of LCM (Laser Capture Microdissection) epithelial cell populations representing prostate cancer progression from benign epithelium to metastatic disease (28). Interestingly, genes in Class 1 show a similar pattern in benign/normal epithelial, PIN (prostatic intra epithelial neoplasia), and localized prostate cancer, but a distinctive pattern in metastatic prostate cancer (Figure 6, left panel). In contrast, genes in Class 2 show similar patterns in all categories (Figure 6, right panel). Since Class 1 is more responsive to androgen, our finding that these genes are more reduced in metastatic samples compared to Class 2 is consistent with previous findings that androgen signaling activity is decreased in metastatic prostate cancer (28). The distinctive pattern in metastatic prostate cancer for Class 1 genes indicates their promising potential as novel biomarkers in delineating metastatic prostate cancer. Specifically, genes in Class 1 that are highly expressed and are hypothesized to be involved in ‘short’ combinatorial long-range regulation were downregulated in metastatic versus localized prostate cancer.Figure 6.


Integrated analysis identifies a class of androgen-responsive genes regulated by short combinatorial long-range mechanism facilitated by CTCF.

Taslim C, Chen Z, Huang K, Huang TH, Wang Q, Lin S - Nucleic Acids Res. (2012)

Genes in Class 1 shows distinctive pattern in metastatic prostate cancer while Class 2 shows less distinctive markings. Color represents log2 ratios of expression. When the expression value is not available, it is denoted by gray color.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3367180&req=5

gks139-F6: Genes in Class 1 shows distinctive pattern in metastatic prostate cancer while Class 2 shows less distinctive markings. Color represents log2 ratios of expression. When the expression value is not available, it is denoted by gray color.
Mentions: Finally, we evaluated the biological significance of the genes (focusing on Class 1) for prostate cancer progression. We assess the expression of these genes in the analysis of LCM (Laser Capture Microdissection) epithelial cell populations representing prostate cancer progression from benign epithelium to metastatic disease (28). Interestingly, genes in Class 1 show a similar pattern in benign/normal epithelial, PIN (prostatic intra epithelial neoplasia), and localized prostate cancer, but a distinctive pattern in metastatic prostate cancer (Figure 6, left panel). In contrast, genes in Class 2 show similar patterns in all categories (Figure 6, right panel). Since Class 1 is more responsive to androgen, our finding that these genes are more reduced in metastatic samples compared to Class 2 is consistent with previous findings that androgen signaling activity is decreased in metastatic prostate cancer (28). The distinctive pattern in metastatic prostate cancer for Class 1 genes indicates their promising potential as novel biomarkers in delineating metastatic prostate cancer. Specifically, genes in Class 1 that are highly expressed and are hypothesized to be involved in ‘short’ combinatorial long-range regulation were downregulated in metastatic versus localized prostate cancer.Figure 6.

Bottom Line: In this study, we carried out an integrated analysis combining several types of high-throughput data, including genome-wide distribution data of H3K4 di-methylation (H3K4me2), CCCTC binding factor (CTCF), AR and FoxA1 cistrome data as well as androgen-regulated gene expression data.We found that a subset of androgen-responsive genes was significantly enriched near AR/H3K4me2 overlapping regions and FoxA1 binding sites within the same CTCF block.Our results suggest a relatively short combinatorial long-range regulation mechanism facilitated by CTCF blocking.

View Article: PubMed Central - PubMed

Affiliation: Department of Statistics, The Ohio State University, Columbus, OH 43210, USA.

ABSTRACT
Recently, much attention has been given to elucidate how long-range gene regulation comes into play and how histone modifications and distal transcription factor binding contribute toward this mechanism. Androgen receptor (AR), a key regulator of prostate cancer, has been shown to regulate its target genes via distal enhancers, leading to the hypothesis of global long-range gene regulation. However, despite numerous flows of newly generated data, the precise mechanism with respect to AR-mediated long-range gene regulation is still largely unknown. In this study, we carried out an integrated analysis combining several types of high-throughput data, including genome-wide distribution data of H3K4 di-methylation (H3K4me2), CCCTC binding factor (CTCF), AR and FoxA1 cistrome data as well as androgen-regulated gene expression data. We found that a subset of androgen-responsive genes was significantly enriched near AR/H3K4me2 overlapping regions and FoxA1 binding sites within the same CTCF block. Importantly, genes in this class were enriched in cancer-related pathways and were downregulated in clinical metastatic versus localized prostate cancer. Our results suggest a relatively short combinatorial long-range regulation mechanism facilitated by CTCF blocking. Under such a mechanism, H3K4me2, AR and FoxA1 within the same CTCF block combinatorially regulate a subset of distally located androgen-responsive genes involved in prostate carcinogenesis.

Show MeSH
Related in: MedlinePlus