Distinct function of 2 chromatin remodeling complexes that share a common subunit, Williams syndrome transcription factor (WSTF)

ArticleinProceedings of the National Academy of Sciences 106(23):9280-5 · July 2009with34 Reads
DOI: 10.1073/pnas.0901184106 · Source: PubMed
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.
    • "GTF2IRD1 and GTF2I, have been implicated in the cause of craniofacial dysmorphism in Williams–Beuren syndrome and there is evidence of dosage-sensitivity (Tassabehji et al. 2006). BAZ1B has also been implicated in craniofacial development in Williams–Beuren syndrome (Ashe et al. 2008), although its role is still unclear (Yoshimura et al. 2009). Dosage sensitivity of CREBBP was established by the identification of low-level mosaic individuals with a typical Rubinstein–Taybi syndrome phenotype (Gervasini et al. 2007). "
    [Show abstract] [Hide abstract] ABSTRACT: Sequencing technology is increasingly demonstrating the impact of genomic copy number variation (CNV) on phenotypes. Opposing variation in growth, head size, cognition and behaviour is known to result from deletions and reciprocal duplications of some genomic regions. We propose normative inversion of face shape, opposing difference from a matched norm, as a basis for investigating the effects of gene dosage on craniofacial development. We use dense surface modelling techniques to match any face (or part of a face) to a facial norm of unaffected individuals of matched age, sex and ethnicity and then we reverse the individual’s face shape differences from the matched norm to produce the normative inversion. We demonstrate for five genomic regions, 4p16.3, 7q11.23, 11p15, 16p13.3 and 17p11.2, that such inversion for individuals with a duplication or (epi)-mutation produces facial forms remarkably similar to those associated with a deletion or opposite (epi-)mutation of the same region, and vice versa. The ability to visualise and quantify face shape effects of gene dosage is of major benefit for determining whether a CNV is the cause of the phenotype of an individual and for predicting reciprocal consequences. It enables face shape to be used as a relatively simple and inexpensive functional analysis of the gene(s) involved. Electronic supplementary material The online version of this article (doi:10.1007/s00439-014-1455-z) contains supplementary material, which is available to authorized users.
    Full-text · Article · Jun 2014
    • "WBS patients experience an array of symptoms including cardiac defects, cognitive impairment, hypercalcaemia, growth deficiencies, and a distinct craniofacial phenotype [32-34]. Stemming from studies performed in mouse and cell lines, WSTF has been implicated as a key contributor to many of the phenotypes seen in WBS patients, despite the number of other genes that are also deficient [16,35,36]. It is unclear, however, which specific gene deficiencies contribute to each symptom; a problem common to all contiguous gene deletion disorders. "
    [Show abstract] [Hide abstract] ABSTRACT: Williams syndrome transcription factor (WSTF) is a multifaceted protein that is involved in several nuclear processes, including replication, transcription, and the DNA damage response. WSTF participates in a chromatin-remodeling complex with the ISWI ATPase, SNF2H, and is thought to contribute to the maintenance of heterochromatin, including at the human inactive X chromosome (Xi). WSTF is encoded by BAZ1B, and is one of twenty-eight genes that are hemizygously deleted in the genetic disorder Williams-Beuren syndrome (WBS). To explore the function of WSTF, we performed zinc finger nuclease-assisted targeting of the BAZ1B gene and isolated several independent knockout clones in human cells. Our results show that, while heterochromatin at the Xi is unaltered, new inappropriate areas of heterochromatin spontaneously form and resolve throughout the nucleus, appearing as large DAPI-dense staining blocks, defined by histone H3 lysine-9 trimethylation and association of the proteins heterochromatin protein 1 and structural maintenance of chromosomes flexible hinge domain containing 1. In three independent mutants, the expression of a large number of genes were impacted, both up and down, by WSTF loss. Given the inappropriate appearance of regions of heterochromatin in BAZ1B knockout cells, it is evident that WSTF performs a critical role in maintaining chromatin and transcriptional states, a property that is likely compromised by WSTF haploinsufficiency in WBS patients.
    Full-text · Article · Oct 2013
    • "Results gained from a recently reported mouse model with targeted deletion of Baz1b, indicate that deletion of this gene may account for these defects. BAZ1B is located within the wBS common deleted region, and homozygous Baz1b −/− mice exhibit a range of cardiovascular defects, which include ASD, vSD, trabeculation defects, coarctation of the aorta (COA), hypoplastic pharyngeal arch artery and a low frequency of DORv [187] . BAZ1B (also known as WSTF) acts as a subunit in three ATP-dependent chromatin remodeling complexes ; the wSTF including nucleosome assembly complex (wINAC) [188], the wICH complex (wSTF-ISwI chromatin remodeling complex) [189] and the B-wICH complex [190]. "
    [Show abstract] [Hide abstract] ABSTRACT: Congenital heart disease (CHD) affects nearly 1 % of the population. It is a complex disease, which may be caused by multiple genetic and environmental factors. Studies in human genetics have led to the identification of more than 50 human genes, involved in isolated CHD or genetic syndromes, where CHD is part of the phenotype. Furthermore, mapping of genomic copy number variants and exome sequencing of CHD patients have led to the identification of a large number of candidate disease genes. Experiments in animal models, particularly in mice, have been used to verify human disease genes and to gain further insight into the molecular pathology behind CHD. The picture emerging from these studies suggest that genetic lesions associated with CHD affect a broad range of cellular signaling components, from ligands and receptors, across down-stream effector molecules to transcription factors and co-factors, including chromatin modifiers.
    Full-text · Article · Aug 2013
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