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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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(A) Cartoon illustration of various blocks. Bar: CTCF binding sites; rectangle: AR binding site; hexagon: FoxA1 binding site; line: H3K4me2 enrichment site. A genomic region with CTCF binding sites as borders is defined as a block. The first block from the left containing a RefSeq gene, AR binding site and H3K4me2 enrichment is both an AR block and a H3K4me2 block. The second block is referred to as FoxA1 block since it contains only FoxA1 binding site. The last block is both an AR-H3K4me2 block (AR binding site overlap with H3K4me2 enrichment) and a FoxA1 block. (B) Distribution of length of blocks in kb. In addition to the overall distribution, the figure also shows the distribution of blocks containing AR binding sites (AR blocks), blocks containing FoxA1 (FoxA1 blocks), blocks containing at least one responsive genes (responsive blocks), and blocks consist of only non-responsive genes (non-responsive genes) in LNCaP cell line 4 h after being induced by androgen.
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gks139-F1: (A) Cartoon illustration of various blocks. Bar: CTCF binding sites; rectangle: AR binding site; hexagon: FoxA1 binding site; line: H3K4me2 enrichment site. A genomic region with CTCF binding sites as borders is defined as a block. The first block from the left containing a RefSeq gene, AR binding site and H3K4me2 enrichment is both an AR block and a H3K4me2 block. The second block is referred to as FoxA1 block since it contains only FoxA1 binding site. The last block is both an AR-H3K4me2 block (AR binding site overlap with H3K4me2 enrichment) and a FoxA1 block. (B) Distribution of length of blocks in kb. In addition to the overall distribution, the figure also shows the distribution of blocks containing AR binding sites (AR blocks), blocks containing FoxA1 (FoxA1 blocks), blocks containing at least one responsive genes (responsive blocks), and blocks consist of only non-responsive genes (non-responsive genes) in LNCaP cell line 4 h after being induced by androgen.

Mentions: Next, we divided the genome into distinct CTCF blocks to study the combinatorial relationship of AR-mediated gene expression with other factors within and across different blocks. Since these 11 553 common CTCF binding sites are evolutionary conserved [see Supplementary Figure S2 and Reference (20)], they are used to partition the human genome. These sites demarcate the genome into 11 576 blocks of varying sizes with a median of 81 kb and an IQR (interquartile range) of 198 kb. Here, a block is defined as a genomic region with two consecutive CTCF-bound sites as borders and include the beginning (ending) of each chromosome to (from) the first (last) binding sites on the chromosome (Figure 1A).Figure 1.


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)

(A) Cartoon illustration of various blocks. Bar: CTCF binding sites; rectangle: AR binding site; hexagon: FoxA1 binding site; line: H3K4me2 enrichment site. A genomic region with CTCF binding sites as borders is defined as a block. The first block from the left containing a RefSeq gene, AR binding site and H3K4me2 enrichment is both an AR block and a H3K4me2 block. The second block is referred to as FoxA1 block since it contains only FoxA1 binding site. The last block is both an AR-H3K4me2 block (AR binding site overlap with H3K4me2 enrichment) and a FoxA1 block. (B) Distribution of length of blocks in kb. In addition to the overall distribution, the figure also shows the distribution of blocks containing AR binding sites (AR blocks), blocks containing FoxA1 (FoxA1 blocks), blocks containing at least one responsive genes (responsive blocks), and blocks consist of only non-responsive genes (non-responsive genes) in LNCaP cell line 4 h after being induced by androgen.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

gks139-F1: (A) Cartoon illustration of various blocks. Bar: CTCF binding sites; rectangle: AR binding site; hexagon: FoxA1 binding site; line: H3K4me2 enrichment site. A genomic region with CTCF binding sites as borders is defined as a block. The first block from the left containing a RefSeq gene, AR binding site and H3K4me2 enrichment is both an AR block and a H3K4me2 block. The second block is referred to as FoxA1 block since it contains only FoxA1 binding site. The last block is both an AR-H3K4me2 block (AR binding site overlap with H3K4me2 enrichment) and a FoxA1 block. (B) Distribution of length of blocks in kb. In addition to the overall distribution, the figure also shows the distribution of blocks containing AR binding sites (AR blocks), blocks containing FoxA1 (FoxA1 blocks), blocks containing at least one responsive genes (responsive blocks), and blocks consist of only non-responsive genes (non-responsive genes) in LNCaP cell line 4 h after being induced by androgen.
Mentions: Next, we divided the genome into distinct CTCF blocks to study the combinatorial relationship of AR-mediated gene expression with other factors within and across different blocks. Since these 11 553 common CTCF binding sites are evolutionary conserved [see Supplementary Figure S2 and Reference (20)], they are used to partition the human genome. These sites demarcate the genome into 11 576 blocks of varying sizes with a median of 81 kb and an IQR (interquartile range) of 198 kb. Here, a block is defined as a genomic region with two consecutive CTCF-bound sites as borders and include the beginning (ending) of each chromosome to (from) the first (last) binding sites on the chromosome (Figure 1A).Figure 1.

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