title: Corepressive action of CBP on androgen receptor transactivation in pericentric heterochromatin in a Drosophila experimental model system.
abstract: Ligand-bound nuclear receptors (NR) activate transcription of the target genes. This activation is coupled with histone modifications and chromatin remodeling through the function of various coregulators. However, the nature of the dependence of a NR coregulator action on the presence of the chromatin environment at the target genes is unclear. To address this issue, we have developed a modified position effect variegation experimental model system that includes an androgen-dependent reporter transgene inserted into either a pericentric heterochromatin region or a euchromatic region of Drosophila chromosome. Human androgen receptor (AR) and its constitutively active truncation mutant (AR AF-1) were transcriptionally functional in both chromosomal regions. Predictably, the level of AR-induced transactivation was lower in the pericentric heterochromatin. In genetic screening for AR AF-1 coregulators, Drosophila CREB binding protein (dCBP) was found to corepress AR transactivation at the pericentric region whereas it led to coactivation in the euchromatic area. Mutations of Sir2 acetylation sites or deletion of the CBP acetyltransferase domain abrogated dCBP corepressive action for AR at heterochromatic areas in vivo. Such a CBP corepressor function for AR was observed in the transcriptionally silent promoter of an AR target gene in cultured mammalian cells. Thus, our findings suggest that the action of NR coregulators may depend on the state of chromatin at the target loci.
authors.affiliation: The Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Takeyama
authors.forename: Shun
authors.initials: S
authors.lastname: Sawatsubashi
authors.forename: Saya
authors.initials: S
authors.lastname: Ito
authors.forename: Eriko
authors.initials: E
authors.lastname: Suzuki
authors.forename: Kaoru
authors.initials: K
authors.lastname: Yamagata
authors.forename: Masahiko
authors.initials: M
authors.lastname: Tanabe
authors.forename: Shuhei
authors.initials: S
authors.lastname: Kimura
authors.forename: Sally
authors.initials: S
authors.lastname: Fujiyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Ueda
authors.forename: Takuya
authors.initials: T
authors.lastname: Murata
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Matsukawa
authors.forename: Yuko
authors.initials: Y
authors.lastname: Shirode
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Kouzmenko
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Testuya
authors.initials: T
authors.lastname: Tabata
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D050882:CREB-Binding Protein / Q000737:chemistry / Q000378:metabolism*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D055012:Chromosomal Position Effects / Q000235:genetics*; D017124:Conserved Sequence; D029721:Drosophila Proteins / Q000737:chemistry; D004331:Drosophila melanogaster / Q000235:genetics*; D022041:Euchromatin / Q000378:metabolism; D006570:Heterochromatin / Q000378:metabolism*; D006655:Histone Deacetylases / Q000737:chemistry; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D008957:Models, Genetic; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D037761:Sirtuins / Q000737:chemistry; D015533:Transcriptional Activation / Q000235:genetics*
chemical_list: C410798:AR protein, human; D029721:Drosophila Proteins; D022041:Euchromatin; D006570:Heterochromatin; D006657:Histones; D011944:Receptors, Androgen; D012097:Repressor Proteins; D050882:CREB-Binding Protein; C447899:Sirt2 protein, Drosophila; D037761:Sirtuins; D006655:Histone Deacetylases; D008239:Lysine