WSTF deficiency reprograms regulatory networks by linking locus–specific chromatin remodeling to altered isoform expression and misdirected signaling

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ID: 316430
2026
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Abstract
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, 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 establish a mechanistic chain from WSTF-dependent chromatin architecture to co-transcriptional RNA processing integrity, signaling pathway fidelity, and developmental gene program regulation relevant to Williams syndrome.
Reference Key
openalex_W7163895622 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Shahin  Behrouz Sharif, Jonathan H. Dennis
Journal Nucleic Acids Research
Year 2026
DOI
10.1093/nar/gkag602
URL
https://doi.org/10.1093/nar/gkag602
Keywords Keywords not found

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