Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA291760 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description: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 Williams syndrome. 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 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.
2016-01-19 | GSE71664 | GEO
Project description: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. In three independent mutants, the expression of a large number of genes were impacted, both up and down, by WSTF loss. In addition, we found that cells lacking WSTF responded appropriately to vitamin D treatment, a process we expected to be disrupted. 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. Clearly, further exploration is necessary to fully understand the role of WSTF in maintenance of the epigenome and how WSTF haploinsufficiency contributes to the wide array of symptoms exhibited in WBS patients. Samples include three replicate miroarray hybridizations of the parental cells (hTERT-RPE1), three replicates from three independent knock-out clones (D5, F3 and M1), and one set of replicates for a heterozygous mutant clone (A6).
2014-05-21 | E-GEOD-47390 | biostudies-arrayexpress
Project description: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. In three independent mutants, the expression of a large number of genes were impacted, both up and down, by WSTF loss. In addition, we found that cells lacking WSTF responded appropriately to vitamin D treatment, a process we expected to be disrupted. 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. Clearly, further exploration is necessary to fully understand the role of WSTF in maintenance of the epigenome and how WSTF haploinsufficiency contributes to the wide array of symptoms exhibited in WBS patients.
2014-05-21 | GSE47390 | GEO
Project description:Loss of the chromatin remodeler WSTF (BAZ1B), a gene deleted in Williams syndrome, causes reproducible, genome-scale reprogramming of chromatin states and transcript processing that links altered chromatin composition to misprocessed transcripts and aberrant signaling. Using engineered HCT116-WSTFKO cells and patient-derived Williams syndrome cell lines, we combine transcriptome profiling, microscopy, chromatin CUT&RUN, and histone post-translational modification (HPTM)-defined chromatin state modeling to show that WSTF localizes to promoters and gene bodies of actively transcribed loci together with ASH2L and CBP. Loss of WSTF causes depletion of ASH2L/CBP, selective loss of H3K4me2 and multiple acetylation marks, and gain of Polycomb components. This loss results in systematic conversion from a multi-mark active promoter/enhancer chromatin landscape to a hypoacetylated, H3K4me2-depleted, PRC-enriched landscape. These chromatin changes coincide with widespread isoform switching and splicing alterations in genes encoding chromatin regulators and signaling pathways. This WSTF deficiency produces Wnt/β-catenin hyperactivation. A locus-specific example at TCF7L2 demonstrates how gene body loss of active marks drives isoform switching that alters DNA binding domains and decouples stabilized nuclear β-catenin from canonical target engagement. Our results link signaling dysregulation to developmental pathway misregulation consistent with Williams syndrome phenotypes.
2025-12-24 | GSE314624 | GEO
Project description:Loss of the chromatin remodeler WSTF (BAZ1B), a gene deleted in Williams syndrome, causes reproducible, genome-scale reprogramming of chromatin states and transcript processing that links altered chromatin composition to misprocessed transcripts and aberrant signaling. Using engineered HCT116-WSTFKO cells and patient-derived Williams syndrome cell lines, we combine transcriptome profiling, microscopy, chromatin CUT&RUN, and histone post-translational modification (HPTM)-defined chromatin state modeling to show that WSTF localizes to promoters and gene bodies of actively transcribed loci together with ASH2L and CBP. Loss of WSTF causes depletion of ASH2L/CBP, selective loss of H3K4me2 and multiple acetylation marks, and gain of Polycomb components. This loss results in systematic conversion from a multi-mark active promoter/enhancer chromatin landscape to a hypoacetylated, H3K4me2-depleted, PRC-enriched landscape. These chromatin changes coincide with widespread isoform switching and splicing alterations in genes encoding chromatin regulators and signaling pathways. This WSTF deficiency produces Wnt/β-catenin hyperactivation. A locus-specific example at TCF7L2 demonstrates how gene body loss of active marks drives isoform switching that alters DNA binding domains and decouples stabilized nuclear β-catenin from canonical target engagement. Our results link signaling dysregulation to developmental pathway misregulation consistent with Williams syndrome phenotypes.
2025-12-24 | GSE314625 | GEO
Project description:In order to dissect the role of BAZ1B in the paradigmatic craniofacial dysmorphisms that characterize Williams Beuren Syndrome and the simmetrical genetically opposite 7q11.23 duplication syndrome(7dupASD), we selected a large cohort of NCSCs lines (4 from WBS patients, 3 from 7dupASD patients and 4 from control individuals) to perform transcriptomic profiling. These lines show a clear cranial identity signatures which is crucial to pinpoint the disease pathogenesis, We then knocked-down (KD) BAZ1B via RNA interference in all lines across the three genetic conditions, including also NCSCs derived from a particularly informative atypical WBS patient (atWBS) bearing a partial deletion of the region that spares BAZ1B and six additional genes (see paper). In order to establish a high-resolution gradient of BAZ1B dosages, we selected two distinct shRNA against BAZ1B (i.e., sh1 and sh2) along with a scrambled shRNA sequence (hereafter scr) as negative control, for a total of 32 NCSC lines. KD efficiency was evaluated both at the RNA level by quantitative PCR (qPCR), confirming the attainment of the desired gradient with an overall reduction of about 40% for sh1 and 70% for sh2, as well as reduction at the protein level, as detected by Western blot (see the coupled paper).
2020-02-29 | E-MTAB-8455 | biostudies-arrayexpress
Project description:The genetic elements required to tune gene expression are partitioned in active and repressive nuclear condensates. Chromatin compartments include transcriptional clusters whose dynamic establishment and functioning depends on multivalent interactions occurring among transcription factors, cofactors and basal transcriptional machinery. However how chromatin players contribute to the assembly of transcriptional condensates has not been addressed. By interrogating the effect of KMT2D haploinsufficiency in Kabuki Syndrome, we found that MLL4 contributes in the assembly of transcriptional condensates through liquid-liquid phase separation. MLL4 loss-of-function impaired Polycomb-dependent chromatin compartmentalization, altering nuclear architecture. By releasing the nuclear mechanical stress through the inhibition of the mechano-sensor ATR, we re-established the mechano-signaling of mesenchymal stem cells and their commitment towards chondrocytes both in vitro and in vivo. This study supports the notion that in Kabuki Syndrome the haploinsufficiency of MLL4 causes an altered functional partitioning of chromatin, which determines the architecture and mechanical properties of the nucleus.
2020-09-22 | PXD021616 | Pride
Project description:We apply the cellular reprogramming experimental paradigm to two disorders caused by symmetrical copy number variations (CNV) of 7q11.23 and displaying a striking combination of shared as well as symmetrically opposite phenotypes: Williams Beuren syndrome (WBS) and 7q microduplication syndrome (7dup). Through a uniquely large and informative cohort of transgene-free patient-derived induced pluripotent stem cells (iPSC), along with their differentiated derivatives, we find that 7q11.23 CNV disrupt transcriptional circuits in disease-relevant pathways already at the pluripotent state. These alterations are then selectively amplified upon differentiation into disease-relevant lineages, thereby establishing the value of large iPSC cohorts in the elucidation of disease-relevant developmental pathways. In addition, we functionally define the quota of transcriptional dysregulation specifically caused by dosage imbalances in GTF2I (also known as TFII-I), a transcription factor in 7q11.23 thought to play a critical role in the two conditions, which we found associated to key repressive chromatin modifiers. Finally, we created an open-access web-based platform (accessible at http://bio.ieo.eu/wbs/ ) to make accessible our multi-layered datasets and integrate contributions by the entire community working on the molecular dissection of the 7q11.23 syndromes. We differentiated a representative subset of patient-derived iPSC lines into three disease-relevant lineages: dorsal telencephalic progenitors (Neural Progenitor Cells, NPC), Neural Crest Stem Cells (NCSC) and Mesenchymal Stem Cells (MSC). We profiled NCSC and NPC through microarray (current dataset), and MSC through RNA-seq.
2014-12-15 | E-GEOD-63040 | biostudies-arrayexpress
Project description:While psychiatric disorders (e.g., schizophrenia) and autism spectrum disorders (ASD) are typically associated with a deficit in social behavior, the opposite trait of hypersociability is exhibited by individuals with specific neurodevelopmental disorders, e.g., Angelman Syndrome (AS) and Williams-Beuren Syndrome (WBS). We have recently reported that the deletion of the miR379-410 cluster in mice led to hypersocial behavior. To study the roles of this miRNA cluster in the context of WBS, we sent for smallRNA sequencing RNA isolated from isogenic human iPSC-derived neurons harboring a deletion present in Williams-Beuren-Syndrome patients (7q11.23). Specifically, we found that members of the miR379-410 cluster were strikingly overrepresented among downregulated miRNAs in iNeurons harboring a deletion of the WBS critical region. Thus, we obtained the first evidence for the pathophysiological significance of the miR379-410 miRNA cluster in the context of WBS. We conclude that targeting this novel pathway could have therapeutic potential for WBS and other neurodevelopmental conditions characterized by social impairments.
2023-11-15 | GSE247766 | GEO
Project description:SETD1A, a histone methyltransferase, is implicated in schizophrenia through rare loss-of-function mutations. While SETD1A regulates gene expression via histone H3K4 methylation, its influence on broader epigenetic dysregulation remains incompletely understood. We explored the hypothesis that SETD1A haploinsufficiency contributes to neurodevelopmental disruptions associated with schizophrenia risk via alterations in DNA methylation. We profiled DNA methylation in the frontal cortex of Setd1a+/- mice across prenatal and postnatal development using Illumina Mouse Methylation arrays. Differentially methylated positions and regions were identified, and their functional relevance examined through gene and biological annotation. We integrated these findings with transcriptomic and proteomics datasets, and assessed mitochondrial complex I activity to explore potential downstream functional effects. Setd1a haploinsufficiency resulted in widespread hypomethylation of genes related to ribosomal function and RNA processing that persisted across all developmental stages. Setd1a-targeted promoter regions and noncoding small nucleolar RNAs (snoRNAs) were also enriched for differentially methylated sites. Despite the downregulation of mitochondrial gene expression, the same genes were not differentially methylated and complex I activity in Setd1a+/- mice did not differ significantly from controls. Genes overlapping hypomethylated regions were enriched for common genetic associations with schizophrenia. Our findings suggest that SETD1A haploinsufficiency disrupts the epigenetic regulation of ribosomal pathways. These results provide insight into an alternative mechanism through which genetic variation in SETD1A influences developmental and synaptic plasticity, contributing to schizophrenia pathophysiology.
2025-04-22 | GSE295008 | GEO