Nuclear Wiskott–Aldrich syndrome protein co-regulates T cell factor 1-mediated transcription in T cells

Abstract

BackgroundThe Wiskott–Aldrich syndrome protein (WASp) family of actin-nucleating factors are present in the cytoplasm and in the nucleus. The role of nuclear WASp for T cell development remains incompletely defined.MethodsWe performed WASp chromatin immunoprecipitation and deep sequencing (ChIP-seq) in thymocytes and spleen CD4+ T cells.ResultsWASp was enriched at genic and intergenic regions and associated with the transcription start sites of protein-coding genes. Thymocytes and spleen CD4+ T cells showed 15 common WASp-interacting genes, including the gene encoding T cell factor (TCF)12. WASp KO thymocytes had reduced nuclear TCF12 whereas thymocytes expressing constitutively active WASpL272P and WASpI296T had increased nuclear TCF12, suggesting that regulated WASp activity controlled nuclear TCF12. We identify a putative DNA element enriched in WASp ChIP-seq samples identical to a TCF1-binding site and we show that WASp directly interacted with TCF1 in the nucleus.ConclusionsThese data place nuclear WASp in proximity with TCF1 and TCF12, essential factors for T cell development.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0481-6) contains supplementary material, which is available to authorized users.

Dedicator of cytokinesis protein 2 couples with lymphoid enhancer–binding factor 1 to regulate expression of CD21 and B-cell differentiation

“…Recent research has shown that WASP directly interacts with TCF-1 in the nucleus. 11 TCF-1 is a transcriptional factor that is homologous to LEF-1 and expressed in B cells. 9 To examine whether WASP interacted with LEF-1 in B cells, WT B cells were stimulated with sAg, and confocal microscopy and immunoprecipitation assays were performed for WASP and (Fig 5, E) and the MFI of BCR (Fig 5, F), actin (Fig 5, G), and pY ( Fig 5, H) in the contact zone from 3 independent experiments.…”

“…TCF-1 target genes are enriched in Wiskott-Aldrich syndrome protein (WASP)-deficient B cells, and WASP interacts with TCF-1 in the nucleus. 11 Recently, we found WASP protein expression is reduced in dedicator of cytokinesis protein 8-deficient B cells. 12 Loss of WASP, DOCK2, and dedicator of cytokinesis protein 8 all lead to a reduction in numbers of marginal zone (MZ) B cells.…”

Involvement of Actin and Actin-Binding Proteins in Carcinogenesis

“…Moreover, its interaction with the protein characteristic for DSBs (γH2AX) was also confirmed [ 87 ]. WASP may also be involved in the regulation of RNA polymerase II activity [ 88 ]. Additionally, the correlation between WASP and the p53/p21 signaling pathway also plays an important role in carcinogenesis [ 89 ], whereas the relationship between N-WASP and oncogenic KRas was observed in pancreatic ductal adenocarcinoma [ 90 ].…”

Higher Incidence of B Cell Malignancies in Primary Immunodeficiencies: A Combination of Intrinsic Genomic Instability and Exocytosis Defects at the Immunological Synapse

“…In this regard, chromatin immunoprecipitation (ChIP) experiments have revealed an association of WASp with TbxT1 genes (124,125). Moreover, RNA sequencing analysis revealed different genetic regulation in the presence and absence of WASp (126). As WASp lacks DNA binding motifs, it is possible that these effects are in part mediated via its actin polymerization activity.…”

“…Emergence of tools to specifically study actin filaments in the nucleus using specific reporters with nuclear localization signals as well as the presence of filament regulators such as WASp and Arp2/3 in the nucleus have reignited interest in this field. A role for nuclear actin filaments has been described in (1) homologous repair of heterochromatic double strand breaks in Drosophila oocyte where actin nucleation via Arp2/3 generate tracks for myosins to transport heterochromatic double-strand break to the nuclear lamina ( 128 , 129 ), (2) regulating gene expression following serum starvation via N-WASp/RNA polymerase II interactions ( 130 ) and (3) in regulating the expression of key cytokines downstream of T cell receptor engagement ( 126 , 131 ).…”