Wiskott-Aldrich Syndrome Protein Regulates Nuclear Organization, Alternative Splicing and Cell Proliferation
Moresco, James J.
Benitez, Reyna Hernandez-
Kim, Na Young
III, John R. Yates
Esteban, Concepcion Rodriguez
Belmonte, Juan Carlos Izpisua
KAUST DepartmentBiological and Environmental Sciences and Engineering (BESE) Division
Computer Science Program
Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
KAUST Grant NumberBAS/1/1080-01
Permanent link to this recordhttp://hdl.handle.net/10754/631284
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AbstractWiskott-Aldrich syndrome (WAS), caused by mutations in the WASP protein, displaysimmunological dysfunctions and predisposition to cancer. Despite studies in cell linesand mouse models the molecular mechanisms of WAS remain obscure. We generatedinduced pluripotent stem cells (iPSCs) from patients with WAS (WAS-iPSCs) andisogenic gene-corrected iPSCs by genome editing. Immune cells derived from WASiPSCs,genetically engineered B lymphoblastoid cell lines, and patient primarylymphocytes were subjected to imaging, proteomic and transcriptomic analyses. TheWAS-iPSC model not only recapitulated known disease phenotypes but also revealed,for the first time, roles of WASP in the organization of the nucleolus and nuclearspeckles and PML nuclear bodies. WASP interacts with components of the nucleolusand nuclear speckles, including chromatin modifiers and splicing factors. Innate andadaptive immune cells from WAS patients display global dysregulation of cell cycleregulation and alternative splicing. WASP mutation is sufficient to drive an acceleratedcell cycle and tumor-promoting splicing changes. Our data show that WASP acts as atumor suppressor and specific WASP mutants behave as oncogenes and cause cellintrinsicalterations that predispose patients to cancer.
CitationLi M, Suzuki K, Zhou X, Yamauchi T, Moresco JJ, et al. (2018) Wiskott-Aldrich Syndrome Protein Regulates Nuclear Organization, Alternative Splicing and Cell Proliferation. SSRN Electronic Journal. Available: http://dx.doi.org/10.2139/ssrn.3304823.
SponsorsWe would like to thank B. Lubin for advice on hematopoiesis and assistance in cord blood unit procurement; C. Cole, R. Walker, J. Lieu, R. Tonai, M. Swearingen for providing cord blood samples; Y. Zheng for advice on hematopoietic differentiation and assistance on flow cytometry; members of the Belmonte lab for helpful discussions; A. T. Gutiérrez, A. Geobl, R. D. Soligalla and Y. Hishida for technical assistance, L. Mack, J, Olvera, C. O’Connor, E. O'Connor and K. Marquez for help with flow cytometry; D. O’Keefe for critical reading of the manuscript; M. Schwarz, P. Schwarz, C. Xia and X. Zhang for administrative help. Funding: M.L. was supported by grants from the King Abdullah University of Science and Technology. This work was supported by the Waitt Advanced Biophotonics Core Facility of the Salk Institute with funding from NIH-NCI CCSG: P30 014195, NINDS Neuroscience Core Grant and the Waitt Foundation. J.C.I.B. was supported by grants from The Moxie Foundation, G. Harold and Leila Y. Mathers Charitable Foundation, The Leona M. and Harry B. Helmsley Charitable Trust grant #2012-PG-MED002, The Glenn Foundation and Universidad Católica San Antonio de Murcia (UCAM). Work in the laboratory of M.L. was supported by the KAUST Office of Sponsored Research (OSR) under Awards No. BAS/1/1080-01. Author contributions: M.L., K.S. and J.C.I.B conceived the project, designed the experiments and performed data analysis. K.S., T.Y., X.Z, J.J.M., S.D., R.H.B., T.H., N.Y.K, M.M.A., M.K., Y.T., J.X., J.Q., E.A., J.Q., G.L., Z.L., F.Y, C.B., Y.G., C.S., J.R.Y.III., X.D.F., and C.R.E. contributed to project design and conducted the experiments. L.H., C.B., M.S. bioinformatics design, carried out bioinformatics work, and interpreted data. P.C. and F.F. contributed to the design and experiments related to the primary patient samples. M.L. and J.C.I.B. wrote the paper.