Corepressive action of CBP on androgen receptor transactivation in pericentric heterochromatin in a Drosophila experimental model system.
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.
Zhao
Yue
Y
The Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
Takeyama
Ken-ichi
K
Sawatsubashi
Shun
S
Ito
Saya
S
Suzuki
Eriko
E
Yamagata
Kaoru
K
Tanabe
Masahiko
M
Kimura
Shuhei
S
Fujiyama
Sally
S
Ueda
Takashi
T
Murata
Takuya
T
Matsukawa
Hiroyuki
H
Shirode
Yuko
Y
Kouzmenko
Alexander P
AP
Li
Feng
F
Tabata
Testuya
T
Kato
Shigeaki
S
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*
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