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 largely uncovered. Williams syndrome transcription factor (WSTF) was biochemically identified as a major subunit, along with two distinct ATP-dependent chromatin remodeling complexes: WINAC, a SWI/SNF-type complex, and WICH, an ISWI-type complex. Here, WSTF-/- mice were generated in order to investigate its functions in chromatin remodeling in vivo. Loss of WSTF expression results in neonatal lethality, and all WSTF-/-and ~10% of WSTF+/-neonates suffer cardiovascular abnormalities resembling those found in patients carrying autosomal dominant Williams syndrome conceivably due to the inappropriate chromatin reorganization. In vitro analysis revealed that WSTF-/-mouse embryonic fibroblast (MEF) cells showed the impaired transactivation functions of the cardiac transcription activators on Gja5 promoter, but the effects were reversed by overexpression of WINAC components. Likewise inWSTF-/-MEFcells, recruitment of Snf2h, an ISWI ATPase, to Pcna and cell survival after DNA damage are both defective, but ameliorated by overexpression of WICH components. Thus, WSTF is a shared and functionally indispensable subunit of the WICH complex for DNA repair, and the WINAC complexfor transcriptional control.

Program member
Shigeaki Kato (Institute of Molecular and Cellular Biosciences, The University of Tokyo)

Neonatal lethality in mice lacking WSTF.
WSTF is a shared component of two disstinct chromatin remodeling complexes designated WINAC and WICH.