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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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Related in: MedlinePlus

Genes in Class 1 are closer to a transcription factor AR and to FoxA1 binding sites compared to genes in Class 2. The same patterns are observed in both up- and down-regulated genes, although this distance preferential are more obvious for over-expressed genes.
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gks139-F3: Genes in Class 1 are closer to a transcription factor AR and to FoxA1 binding sites compared to genes in Class 2. The same patterns are observed in both up- and down-regulated genes, although this distance preferential are more obvious for over-expressed genes.

Mentions: The two classes indicate two distinct mechanisms of long-range regulation of androgen-responsive genes. In particular, genes in Class 1 correspond to ‘short’ combinatorial long-range regulation that we have hypothesized, whereas the long-range regulation mechanism of genes in Class 2 is less clear, although it is consistent with a long-range regulation mechanism that requires mediation from factor(s) that are located much farther away from the genes being regulated. To elaborate on the effect of distances on the classification of these two classes, we plotted the density function (smoothed using spline function) of the distances, stratified according to classes and up/down regulation of genes (Figure 3). As shown in Figure 3, genes in Class 1 are closer to AR and FoxA1 binding sites compared to those in Class 2 with both up- and down-regulated genes showing similar patterns. This phenomenon is more obviously displayed in upregulated genes.Figure 3.


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 are closer to a transcription factor AR and to FoxA1 binding sites compared to genes in Class 2. The same patterns are observed in both up- and down-regulated genes, although this distance preferential are more obvious for over-expressed genes.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

gks139-F3: Genes in Class 1 are closer to a transcription factor AR and to FoxA1 binding sites compared to genes in Class 2. The same patterns are observed in both up- and down-regulated genes, although this distance preferential are more obvious for over-expressed genes.
Mentions: The two classes indicate two distinct mechanisms of long-range regulation of androgen-responsive genes. In particular, genes in Class 1 correspond to ‘short’ combinatorial long-range regulation that we have hypothesized, whereas the long-range regulation mechanism of genes in Class 2 is less clear, although it is consistent with a long-range regulation mechanism that requires mediation from factor(s) that are located much farther away from the genes being regulated. To elaborate on the effect of distances on the classification of these two classes, we plotted the density function (smoothed using spline function) of the distances, stratified according to classes and up/down regulation of genes (Figure 3). As shown in Figure 3, genes in Class 1 are closer to AR and FoxA1 binding sites compared to those in Class 2 with both up- and down-regulated genes showing similar patterns. This phenomenon is more obviously displayed in upregulated genes.Figure 3.

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