title: Integrated analysis identifies a class of androgen-responsive genes regulated by short combinatorial long-range mechanism facilitated by CTCF.
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.
authors.affiliation: Department of Statistics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Cenny
authors.initials: C
authors.lastname: Taslim
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.forename: Kun
authors.initials: K
authors.lastname: Huang
authors.forename: Tim Hui-Ming
authors.initials: TH
authors.lastname: Huang
authors.forename: Qianben
authors.initials: Q
authors.lastname: Wang
authors.forename: Shili
authors.initials: S
authors.lastname: Lin
mesh_terms: D000728:Androgens / Q000494:pharmacology; D001665:Binding Sites; D000076246:CCCTC-Binding Factor; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006367:HeLa Cells; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D009362:Neoplasm Metastasis; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: D000728:Androgens; D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D006657:Histones; D011944:Receptors, Androgen; D012097:Repressor Proteins