The chromatin-remodeling complex WINAC targets a nuclear receptor to promoters and is impaired in Williams syndrome.
We identified a human multiprotein complex (WINAC) that directly interacts with the vitamin D receptor (VDR) through the Williams syndrome transcription factor (WSTF). WINAC has ATP-dependent chromatin-remodeling activity and contains both SWI/SNF components and DNA replication-related factors. The latter might explain a WINAC requirement for normal S phase progression. WINAC mediates the recruitment of unliganded VDR to VDR target sites in promoters, while subsequent binding of coregulators requires ligand binding. This recruitment order exemplifies that an interaction of a sequence-specific regulator with a chromatin-remodeling complex can organize nucleosomal arrays at specific local sites in order to make promoters accessible for coregulators. Furthermore, overexpression of WSTF could restore the impaired recruitment of VDR to vitamin D regulated promoters in fibroblasts from Williams syndrome patients. This suggests that WINAC dysfunction contributes to Williams syndrome, which could therefore be considered, at least in part, a chromatin-remodeling factor disease.
Kitagawa
Hirochika
H
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, 113-0032, Tokyo, Japan.
Fujiki
Ryoji
R
Yoshimura
Kimihiro
K
Mezaki
Yoshihiro
Y
Uematsu
Yoshikatsu
Y
Matsui
Daisuke
D
Ogawa
Satoko
S
Unno
Kiyoe
K
Okubo
Mataichi
M
Tokita
Akifumi
A
Nakagawa
Takeya
T
Ito
Takashi
T
Ishimi
Yukio
Y
Nagasawa
Hiromichi
H
Matsumoto
Toshio
T
Yanagisawa
Junn
J
Kato
Shigeaki
S
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics* / Q000378:metabolism; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D004261:DNA Replication / Q000235:genetics; D005057:Eukaryotic Cells / Q000378:metabolism*; D005333:Fetus; D005786:Gene Expression Regulation / Q000235:genetics; D005809:Genes, Regulator / Q000235:genetics; D006801:Humans; D046911:Macromolecular Substances; D051379:Mice; D046912:Multiprotein Complexes; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D009707:Nucleosomes / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism; D016196:S Phase / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D018980:Williams Syndrome / Q000235:genetics* / Q000378:metabolism
D002843:Chromatin; D046911:Macromolecular Substances; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D009707:Nucleosomes; D018167:Receptors, Calcitriol; D014157:Transcription Factors