Phosphorylation of Williams syndrome transcription factor by MAPK induces a switching between two distinct chromatin remodeling complexes.
Changes in the environment of a cell precipitate extracellular signals and sequential cascades of protein modification and elicit nuclear transcriptional responses. However, the functional links between intracellular signaling-dependent gene regulation and epigenetic regulation by chromatin-modifying proteins within the nucleus are largely unknown. Here, we describe novel epigenetic regulation by MAPK cascades that modulate formation of an ATP-dependent chromatin remodeling complex, WINAC (WSTF Including Nucleosome Assembly Complex), an SWI/SNF-type complex containing Williams syndrome transcription factor (WSTF). WSTF, a specific component of two chromatin remodeling complexes (SWI/SNF-type WINAC and ISWI-type WICH), was phosphorylated by the stimulation of MAPK cascades in vitro and in vivo. Ser-158 residue in the WAC (WSTF/Acf1/cbpq46) domain, located close to the N terminus of WSTF, was identified as a major phosphorylation target. Using biochemical analysis of a WSTF mutant (WSTF-S158A) stably expressing cell line, the phosphorylation of this residue (Ser-158) was found to be essential for maintaining the association between WSTF and core BAF complex components, thereby maintaining the ATPase activity of WINAC. WINAC-dependent transcriptional regulation of vitamin D receptor was consequently impaired by this WSTF mutation, but the recovery from DNA damage mediated by WICH was not impaired. Our results suggest that WSTF serves as a nuclear sensor of the extracellular signals to fine-tune the chromatin remodeling activity of WINAC. WINAC mediates a previously unknown MAPK-dependent step in epigenetic regulation, and this MAPK-dependent switching mechanism between the two functionally distinct WSTF-containing complexes might underlie the diverse functions of WSTF in various nuclear events.
Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan.
Hiroyuki
H
Oya
Atsushi
A
Yokoyama
Ikuko
I
Yamaoka
Ryoji
R
Fujiki
Masayoshi
M
Yonezawa
Min-Young
MY
Youn
Ichiro
I
Takada
Shigeaki
S
Kato
Hirochika
H
Kitagawa
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry*; D004249:DNA Damage; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
D002843:Chromatin; D014157:Transcription Factors; C116750:BAZ1B protein, human; D000092468:Bromodomain Containing Proteins