A working model for nuclear-WASp actions in reprogramming transcription. Step 1: H3K4me3 trimethylation. Because nuclear-WASp physically and functionally associates with the hMLL/COMPASS complex and histone H3K4 trimethylation,^2,3  the model proposes that WH1 mutants disrupt recruitment of MLL-enriched complex and the subsequent inscription of H3K4me3 mark at WASp-target gene promoters. Step 2: Recruitment of CRCs to H3K4me3-tagged nucleosome. Because the human SWR1-like protein EP400 favors binding promoters that are enriched with H3K4me3-marked nucleosomes,¹⁵  the model proposes that WASp regulates EP400 binding to chromatin in T_H1 cells through its previously described effect on H3K4me3 modification.²  WH1 mutations disrupt this function of WASp at its target loci. Step 3: EP400-dependent H2A-to-H2A.Z exchange. Recruitment of EP400 to H3K4me3-marked chromatin catalyzes local H2A-to-H2A.Z exchange, which promotes promoter decompaction. Because the augmented recruitment of SWI/SNF occurs at genomic sites containing H2A.Z-tagged nucleosomes,³⁹  the model proposes that WH1 mutants disrupt the initial H2A.Z-driven chromatin-remodeling and consequently also the deposition of SWI/SNF-like BAF subunits, which in turn affects higher-order chromatin reorganization and RNA polymerase II recruitment.^18,24  Step 4: Recruitment of sequence-specific transcription factors (TFs). WH1 mutants disrupt recruitment of Notch-signal transduction components and NF-κB(p65) at the hBRM target loci in T_H1 cells. Step 5: Transcription elongation. EP400-dependent H2A.Z deposition functions also relieve the RNA Pol II “pause” at +1 nucleosome.^43,44  We propose that WH1 mutants, through their effects on EP400 and H2A-to-H2A.Z exchange, disrupt recruitment of elongating Pol II (CTD-Ser2) and CDK9 (PTEF-b subunit), protein complexes that actuate productive 5′>3′ transcription elongation. The disease model of WAS/XLT proposes that certain WAS mutations could impair one or multiple steps in this processive event, leading to a spectrum of defects that could manifest in either total loss of gene transcription or some gradations of it, which we postulate lends the immunologic basis for cross-phenotype effects and symptom heterogeneity in XLT/WAS.