title: Hormone-induced and DNA demethylation-induced relief of a tissue-specific and developmentally regulated block in transcriptional elongation.
abstract: Genome-wide studies have revealed that genes commonly have a high density of RNA polymerase II just downstream of the transcription start site. This has raised the possibility that genes are commonly regulated by transcriptional elongation, but this remains largely untested in vivo, particularly in vertebrates. Here, we show that the proximal promoter from the Rhox5 homeobox gene recruits polymerase II and begins elongating in all tissues and cell lines that we tested, but it only completes elongation in a tissue-specific and developmentally regulated manner. Relief of the elongation block is associated with recruitment of the elongation factor P-TEFb, the co-activator GRIP1, the chromatin remodeling factor BRG1, and specific histone modifications. We provide evidence that two mechanisms relieve the elongation block at the proximal promoter: demethylation and recruitment of androgen receptor. Together, our findings support a model in which promoter proximal pausing helps confer tissue-specific and developmental gene expression through a mechanism regulated by DNA demethylation-dependent nuclear hormone receptor recruitment.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, the Greehey Children's Cancer Research Institute, Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas 78229.
authors.forename: Manjeet K
authors.initials: MK
authors.lastname: Rao
authors.affiliation: From the Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Yuiko
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: the Department of Reproductive Medicine, University of California at San Diego, La Jolla, California 92037, the Institute of Genomic Medicine, University of California at San Diego, La Jolla, California 92093, and.
authors.forename: Marcy E
authors.initials: ME
authors.lastname: Richardson
authors.affiliation: the Greehey Children's Cancer Research Institute, Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas 78229.
authors.forename: Subbarayalu
authors.initials: S
authors.lastname: Panneerdoss
authors.affiliation: From the Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Anjana
authors.initials: A
authors.lastname: Bhardwaj
authors.affiliation: the Department of Reproductive Medicine, University of California at San Diego, La Jolla, California 92037, the Institute of Genomic Medicine, University of California at San Diego, La Jolla, California 92093, and.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Ward
authors.affiliation: From the Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Sreenath
authors.initials: S
authors.lastname: Shanker
authors.affiliation: From the Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, the Department of Reproductive Medicine, University of California at San Diego, La Jolla, California 92037, the Institute of Genomic Medicine, University of California at San Diego, La Jolla, California 92093, and.
authors.forename: Anilkumar
authors.initials: A
authors.lastname: Bettegowda
authors.affiliation: From the Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, the Department of Reproductive Medicine, University of California at San Diego, La Jolla, California 92037, the Institute of Genomic Medicine, University of California at San Diego, La Jolla, California 92093, and mfwilkinson@ucsd.edu.
authors.forename: Miles F
authors.initials: MF
authors.lastname: Wilkinson
mesh_terms: D000728:Androgens / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D019175:DNA Methylation; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000254:growth & development / Q000378:metabolism; D008297:Male; D051379:Mice; D009928:Organ Specificity; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012319:RNA Polymerase II / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012669:Seminal Vesicles / Q000254:growth & development / Q000378:metabolism; D013737:Testis / Q000254:growth & development / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology*; D061805:Transcription Elongation, Genetic / Q000187:drug effects*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000728:Androgens; D006657:Histones; D018398:Homeodomain Proteins; D011944:Receptors, Androgen; D014157:Transcription Factors; D013739:Testosterone; D042925:Positive Transcriptional Elongation Factor B; D012319:RNA Polymerase II
keywords: Androgen Receptor; DNA Methylation; Hormone; Testosterone; Transcriptional Elongation; Transcriptional Regulation