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WSTF deficiency reprograms regulatory networks by linking locus‑specific chromatin remodeling to altered isoform expression and misdirected signaling [mRNA-seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE314625 | GEO | 2025/12/24

REPOSITORIES: GEO

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WSTF deficiency reprograms regulatory networks by linking locus‑specific chromatin remodeling to altered isoform expression and misdirected signaling [CUT&Run]

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.

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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).

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