Disruption of hSWI/SNF complexes in T cells by WAS mutations distinguishes X-linked thrombocytopenia from Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome (WAS), an immunodeficiency disorder, and X-linked thrombocytopenia (XLT), a bleeding disorder, both arise from nonsynonymous mutations in WAS, which encodes a hematopoietic-specific WASp. Intriguingly, XLT evolves into WAS in some patients but not in others; yet the biological basis for this cross-phenotype (CP) effect remains unclear. Using human T-helper (T_H) cells expressing different diseasecausing WASmutations, we demonstrated that hSWI/SNF-like complexes require nuclear-WASp to execute their chromatin-remodeling activity at promoters of WASp-target, immune function genes during T_H1 differentiation. Hot-spot WAS mutations Thr45Met and Arg86Cys, which result in XLT-to-WAS disease progression, impair recruitment of hBRM-but not BRG1-enriched BAF complexes to IFNG and TBX21 promoters. Moreover, promoter enrichment of histone H2A.Z and its catalyzing enzyme EP400 are both impaired. Consequently, activation of Notch signaling, a hBRM-regulated event, and its downstream effector NF-κB are both compromised, along with decreased accessibility of nucleosomal DNA and inefficient transcription-elongation of WASp-target T_H1 genes. In contrast, patient mutations Ala236Gly and Arg477Lys that manifest in XLT without progressing to WAS do not disrupt chromatin remodeling or transcriptional reprogramming of T_H1 genes. Our study defines an indispensable relationship between nuclear-WASp-and hSWI/SNF-complexes in gene activation and reveals molecular distinctions in T_H cells that might contribute to disease severity in the XLT/WAS clinical spectrum.