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 ≈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.

Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits

“…Although this mouse line is not a true knockout, and thus we cannot know a priori whether it recapitulates the assumed Baz1b haploinsufficieny seen in WBS cell lines, this substitution resulted in reduced protein level compared with its wild-type countepart. 26 Notably, mice homozygous for this mutation died within the first week of life, similar to the Baz1b knock-out mice described inYoshimura et al 27 Baz1b heterozygote mice present slightly narrower and shorter craniums compared with wild-type mice as well as reduced size of the posterior region of the lower jaw, indicating a role for Baz1b in the craniofacial development. Moreover, the reduction of the Baz1b protein level produces some craniofacial features similar to those shown by typical WBS patients, such as a small upturned nose with flat nasal bridge, malocclusion, bitemporal narrowing, and prominent forehead.…”

Phosphorylation of Williams Syndrome Transcription Factor by MAPK Induces a Switching between Two Distinct Chromatin Remodeling Complexes

“…WSTF, a component of WINAC, is indispensable for gene regulation by VDR through its chromatin remodeling activity (2,3,21,22). The physiological role of this complex has been clarified in heart development as well as calcium metabolism through analysis of WSTF-deficient mice that lack WINAC-mediated regulation of transcription (3). WSTF constitutes another complex designated WICH (WSTF-ISWI chromatin remodeling complex) (23).…”

“…Vitamin D receptor (VDR) 3 is a member of the steroid/thyroid hormone nuclear receptor superfamily regulating bone metabolism, calcium homeostasis, and cell differentiation by binding with 1␣,25-dihydroxyvitamin D 3 (D3), a physiologi-cally active form of vitamin D (15)(16)(17). Like other nuclear receptors, VDR serves as a ligand-dependent transcription factor that requires distinct classes of co-regulators and multiprotein co-regulator complexes to initiate D3-induced chromatin reorganization (18).…”

Epigenetic landscape and miRNA involvement during neural crest development

“…Several studies support the idea that WSTF contributes to NC development. In Xenopus embryos, WSTF expression overlaps with NC markers (Cus et al, 2006), and WSTF-null mice show defects in heart and craniofacial skeleton (Yoshimura et al, 2009). Moreover, WSTF-depleted embryos evidenced normal NC induction/ specification, but presented a severe defect on migration and/or maintenance of NC cells (Barnett et al, 2012).…”