WSTF deficiency reprograms regulatory networks by linking locus-specific chromatin remodeling to altered isoform expression and misdirected signaling [CUT&Run]
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: CUT&RUN of WSTF, SNF2H, ASH2L, CBP, EZH2, CBX4, LaminB, H2AK119ub, H3K4me1, H3K4me2, H3K4me3, H3K9ac, H3K9me3, H3K9ac, H3K14ac, H3K27me3, H3K27ac, H3K36me2, H4K5ac, H4K8ac, H4K12ac, and H4K20me1 in two technical replicates of HCT116 cells CUT&RUN of SNF2H, ASH2L, CBP, EZH2, CBX4, LaminB, H2AK119ub, H3K4me1, H3K4me2, H3K4me3, H3K9ac, H3K9me3, H3K9ac, H3K14ac, H3K27me3, H3K27ac, H3K36me2, H4K5ac, H4K8ac, H4K12ac, and H4K20me1 in two biological replicates of HCT116-WSTFKO cells