Figure 5
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 TH1 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 TH1 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.

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 TH1 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 TH1 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.

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