Haploinsufficiency of BAZ1B contributes to Williams syndrome through transcriptional dysregulation of neurodevelopmental pathways

Abstract

Williams syndrome (WS) is a neurodevelopmental disorder caused by a genomic deletion of ∼28 genes that results in a cognitive and behavioral profile marked by overall intellectual impairment with relative strength in expressive language and hypersocial behavior. Advancements in protocols for neuron differentiation from induced pluripotent stem cells allowed us to elucidate the molecular circuitry underpinning the ontogeny of WS. In patient-derived stem cells and neurons, we determined the expression profile of the Williams-Beuren syndrome critical region-deleted genes and the genome-wide transcriptional consequences of the hemizygous genomic microdeletion at chromosome 7q11.23. Derived neurons displayed disease-relevant hallmarks and indicated novel aberrant pathways in WS neurons including over-activated Wnt signaling accompanying an incomplete neurogenic commitment. We show that haploinsufficiency of the ATP-dependent chromatin remodeler, BAZ1B, which is deleted in WS, significantly contributes to this differentiation defect. Chromatin-immunoprecipitation (ChIP-seq) revealed BAZ1B target gene functions are enriched for neurogenesis, neuron differentiation and disease-relevant phenotypes. BAZ1B haploinsufficiency caused widespread gene expression changes in neural progenitor cells, and together with BAZ1B ChIP-seq target genes, explained 42% of the transcriptional dysregulation in WS neurons. BAZ1B contributes to regulating the balance between neural precursor self-renewal and differentiation and the differentiation defect caused by BAZ1B haploinsufficiency can be rescued by mitigating over-active Wnt signaling in neural stem cells. Altogether, these results reveal a pivotal role for BAZ1B in neurodevelopment and implicate its haploinsufficiency as a likely contributor to the neurological phenotypes in WS.

Clinical application of chromosomal microarray analysis for the prenatal diagnosis of chromosomal abnormalities and copy number variations in fetuses with congenital heart disease

“…We identified recurrent rare CNVs that overlapped with the same region that was reported in previous studies, but we did not include genes previously listed as CHD‐related candidate genes, suggesting that additional genes in these regions may be important for the cardiac phenotype. For example, our CNVs were at the 1q21.2 region but did not include the GJA5 gene.…”

RNA-sequencing of a mouse-model of spinal muscular atrophy reveals tissue-wide changes in splicing of U12-dependent introns

“…Another gene with an intron consistently affected by decreased SMN levels both in SMA mice and the HeLa knock-down experiment was Baz1b , a transcription factor and regulator of chromatin structure recently shown to regulate the transcription of neurodevelopmental genes (85). Furthermore, Baz1b is involved in DNA damage response (86), and DNA damage is increased in SMA mouse models, including the ‘Taiwanese’ model used in this study (87).…”

Exome sequencing of 85 Williams–Beuren syndrome cases rules out coding variation as a major contributor to remaining variance in social behavior

“…Studying rare events that result in atypical deletions sparing different genes in the Williams syndrome critical region (WSCR), as well as single gene knock out studies in mouse models, have suggested that GTF2IRD1 and BAZ1B play a role in the craniofacial abnormalities (Ashe et al, 2008;Tassabehji et al, 2005). Likewise, the genes STX1A, LIMK1, CYLN2, BAZ1B, GTF2IRD1, and GTF2I (Dai et al, 2009;Fujiwara, Sanada, Kofuji, & Akagawa, 2016;Gao et al, 2010;van Hagen et al, 2007;Hoogenraad et al, 2002;Lalli et al, 2016;Meng et al, 2002;Morris et al, 2003;Sakurai et al, 2011) have been implicated in the cognitive and behavioral phenotypes.…”