Nucleosomal remodeling defects at gene promoters underlie cross-phenotype effects in X-linked thrombocytopenia/Wiskott-Aldrich syndrome (IRM6P.655)

Loss-of-function mutations in Wiskott-Aldrich-Syndrome (WAS) gene associate with either X-linked thrombocytopenia (XLT) or XLT that progresses to immunodeficiency, yet the biological basis for gene-pleiotropy remains unknown. WASp, the protein deficient in WAS, generates F-actin in the cytosol via VCA-domain and supports transcription in the nucleus, the latter by an unknown mechanism. We report that nuclear-WASp, independently of its VCA-domain, is required for the recruitment of BAF47, BAF170, and EP400 to IFNG and TBX21 promoters during TH1-differentiation, but not to IL4 or GATA3 during TH2-differentiation. XLT-causing Thr45Met mutation that progresses to immunodeficiency, impairs recruitment of the above chromatin-remodelers, NF-κB(p65), and STAT1 to TH1-gene promoters, which show paucity of H2A.Z containing nucleosomes, and are therefore sub-optimally transcribed. Dissimilarly, Ala236Gly and Arg477Lys mutations that manifest in XLT without progressing to immunodeficiency do not impair TH1-transcriptional reprogramming. We identify a functional link between nuclear-WASp and SWI/SNF-complexes in T lymphocytes, perturbation of which provides a mechanism for the development of clinical crossphenotypes in human XLT/WAS.