title: Distinct function of 2 chromatin remodeling complexes that share a common subunit, Williams syndrome transcription factor (WSTF).
abstract: A number of nuclear complexes modify chromatin structure and operate as functional units. However, the in vivo role of each component within the complexes is not known. ATP-dependent chromatin remodeling complexes form several types of protein complexes, which reorganize chromatin structure cooperatively with histone modifiers. Williams syndrome transcription factor (WSTF) was biochemically identified as a major subunit, along with 2 distinct complexes: WINAC, a SWI/SNF-type complex, and WICH, an ISWI-type complex. Here, WSTF(-/-) mice were generated to investigate its function in chromatin remodeling in vivo. Loss of WSTF expression resulted in neonatal lethality, and all WSTF(-/-) neonates and approximately 10% of WSTF(+/-) neonates suffered cardiovascular abnormalities resembling those found in autosomal-dominant Williams syndrome patients. Developmental analysis of WSTF(-/-) embryos revealed that Gja5 gene regulation is aberrant from E9.5, conceivably because of inappropriate chromatin reorganization around the promoter regions where essential cardiac transcription factors are recruited. In vitro analysis in WSTF(-/-) mouse embryonic fibroblast (MEF) cells also showed impaired transactivation functions of cardiac transcription activators on the Gja5 promoter, but the effects were reversed by overexpression of WINAC components. Likewise in WSTF(-/-) MEF cells, recruitment of Snf2h, an ISWI ATPase, to PCNA and cell survival after DNA damage were both defective, but were ameliorated by overexpression of WICH components. Thus, the present study provides evidence that WSTF is shared and is a functionally indispensable subunit of the WICH complex for DNA repair and the WINAC complex for transcriptional control.
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Kimihiro
authors.initials: K
authors.lastname: Yoshimura
authors.forename: Hirochika
authors.initials: H
authors.lastname: Kitagawa
authors.forename: Ryoji
authors.initials: R
authors.lastname: Fujiki
authors.forename: Masahiko
authors.initials: M
authors.lastname: Tanabe
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Takezawa
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takada
authors.forename: Ikuko
authors.initials: I
authors.lastname: Yamaoka
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Yonezawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kondo
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Furutani
authors.forename: Hisato
authors.initials: H
authors.lastname: Yagi
authors.forename: Shin
authors.initials: S
authors.lastname: Yoshinaga
authors.forename: Takeyoshi
authors.initials: T
authors.lastname: Masuda
authors.forename: Toru
authors.initials: T
authors.lastname: Fukuda
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Kanae
authors.initials: K
authors.lastname: Ebihara
authors.forename: Dean Y
authors.initials: DY
authors.lastname: Li
authors.forename: Rumiko
authors.initials: R
authors.lastname: Matsuoka
authors.forename: Jun K
authors.initials: JK
authors.lastname: Takeuchi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
mesh_terms: D000818:Animals; D018376:Cardiovascular Abnormalities / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly; D004260:DNA Repair; D004261:DNA Replication; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D051379:Mice; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D014157:Transcription Factors; C485505:Baz1b protein, mouse; D000092468:Bromodomain Containing Proteins