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

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/ß-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 ß-catenin from canonical target engagement. Our results link signaling dysregulation to developmental pathway misregulation consistent with Williams syndrome phenotypes. Overall design: mRNAseq profiling of wild-type HCT116 cells and two biological replicates of its WSTF knock-out derivative. mRNAseq profiling of Corriel-derived B-cell lines including GM14295, GM14296, and GM14297, corresponding to William's syndrome family.