ISWI ATPase SMARCA5 regulates differentiation of thymocytes undergoing β-selection

Tomas Zikmund, Juraj Kokavec, Tereza Turkova, Filipp Savvulidi, Helena Paszekova, Sona Vodenkova, Radislav Sedlacek, Arthur I. Skoultchi, Tomas Stopka

Research output: Contribution to journalArticle

Abstract

Development of lymphoid progenitors requires a coordinated regulation of gene expression, DNA replication, and gene rearrangement. Chromatin-remodeling activities directed by SWI/SNF2 superfamily complexes play important roles in these processes. In this study, we used a conditional knockout mouse model to investigate the role of Smarca5, a member of the ISWI subfamily of such complexes, in early lymphocyte development. Smarca5 deficiency results in a developmental block at the DN3 stage of ab thymocytes and pro-B stage of early B cells at which the rearrangement of Ag receptor loci occurs. It also disturbs the development of committed (CD73+) γδ thymocytes. The ab thymocyte block is accompanied by massive apoptotic depletion of b-selected double-negative DN3 cells and premitotic arrest of CD4/CD8 double-positive cells. Although Smarca5-deficient ab T cell precursors that survived apoptosis were able to undergo a successful TCRb rearrangement, they exhibited a highly abnormal mRNA profile, including the persistent expression of CD44 and CD25 markers characteristic of immature cells. We also observed that the p53 pathway became activated in these cells and that a deficiency of p53 partially rescued the defect in thymus cellularity (in contrast to early B cells) of Smarca5-deficient mice. However, the activation of p53 was not primarily responsible for the thymocyte developmental defects observed in the Smarca5 mutants. Our results indicate that Smarca5 plays a key role in the development of thymocytes undergoing β-selection, γδ thymocytes, and also B cell progenitors by regulating the transcription of early differentiation programs.

Original languageEnglish (US)
Pages (from-to)3434-3446
Number of pages13
JournalJournal of Immunology
Volume202
Issue number12
DOIs
StatePublished - Jun 15 2019

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Thymocytes
Adenosine Triphosphatases
Gene Rearrangement
B-Lymphocytes
T-Lymphoid Precursor Cells
Chromatin Assembly and Disassembly
B-Lymphoid Precursor Cells
Gene Expression Regulation
DNA Replication
Knockout Mice
Thymus Gland
Lymphocytes
Apoptosis
Messenger RNA

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Zikmund, T., Kokavec, J., Turkova, T., Savvulidi, F., Paszekova, H., Vodenkova, S., ... Stopka, T. (2019). ISWI ATPase SMARCA5 regulates differentiation of thymocytes undergoing β-selection. Journal of Immunology, 202(12), 3434-3446. https://doi.org/10.4049/jimmunol.1801684

ISWI ATPase SMARCA5 regulates differentiation of thymocytes undergoing β-selection. / Zikmund, Tomas; Kokavec, Juraj; Turkova, Tereza; Savvulidi, Filipp; Paszekova, Helena; Vodenkova, Sona; Sedlacek, Radislav; Skoultchi, Arthur I.; Stopka, Tomas.

In: Journal of Immunology, Vol. 202, No. 12, 15.06.2019, p. 3434-3446.

Research output: Contribution to journalArticle

Zikmund, T, Kokavec, J, Turkova, T, Savvulidi, F, Paszekova, H, Vodenkova, S, Sedlacek, R, Skoultchi, AI & Stopka, T 2019, 'ISWI ATPase SMARCA5 regulates differentiation of thymocytes undergoing β-selection', Journal of Immunology, vol. 202, no. 12, pp. 3434-3446. https://doi.org/10.4049/jimmunol.1801684
Zikmund T, Kokavec J, Turkova T, Savvulidi F, Paszekova H, Vodenkova S et al. ISWI ATPase SMARCA5 regulates differentiation of thymocytes undergoing β-selection. Journal of Immunology. 2019 Jun 15;202(12):3434-3446. https://doi.org/10.4049/jimmunol.1801684
Zikmund, Tomas ; Kokavec, Juraj ; Turkova, Tereza ; Savvulidi, Filipp ; Paszekova, Helena ; Vodenkova, Sona ; Sedlacek, Radislav ; Skoultchi, Arthur I. ; Stopka, Tomas. / ISWI ATPase SMARCA5 regulates differentiation of thymocytes undergoing β-selection. In: Journal of Immunology. 2019 ; Vol. 202, No. 12. pp. 3434-3446.
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