Research ArticleTHYMUS

Tumor suppressor BAP1 is essential for thymic development and proliferative responses of T lymphocytes

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Science Immunology  20 Apr 2018:
Vol. 3, Issue 22, eaal1953
DOI: 10.1126/sciimmunol.aal1953

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Fueling T cell proliferation

Previous studies on BRCA1-associated protein-1 (BAP1) have documented its importance in suppressing development of myeloid leukemia. BAP1 is a deubiquitinase (DUB) that acts on histone H2A monoubiquitinated at Lys119 (H2AK119ub), a chromatin modification associated with gene repression. Arenzana et al. report that BAP1 is essential for development of T cells in the thymus and for promoting peripheral T cell proliferation. The authors report that deletion of BAP1 impaired expression of genes associated with cell cycle progression in thymocytes and in peripheral T cells. In both cases, the effect of BAP1 deletion was dependent on the DUB activity of BAP1, calling for a closer examination of the role of H2AK119ub in T cell development and differentiation.

Abstract

Loss of function of the nuclear deubiquitinating enzyme BRCA1-associated protein-1 (BAP1) is associated with a wide spectrum of cancers. We report that tamoxifen-induced BAP1 deletion in adult mice resulted in severe thymic atrophy. BAP1 was critical for T cell development at several stages. In the thymus, BAP1 was required for progression through the pre–T cell receptor checkpoint. Peripheral T cells lacking BAP1 demonstrated a defect in homeostatic and antigen-driven expansion. Deletion of BAP1 resulted in suppression of E2F target genes and defects in cell cycle progression, which was dependent on the catalytic activity of BAP1, but did not require its interaction with host cell factor-1 (HCF-1). Loss of BAP1 led to increased monoubiquitination of histone H2A at Lys119 (H2AK119ub) throughout the T cell lineage, in particular in immature thymocytes, but did not alter trimethylation of histone H3 at Lys27 (H3K27me3). Deletion of BAP1 also abrogated B cell development in the bone marrow. Our findings uncover a nonredundant function for BAP1 in maintaining the lymphoid lineage.

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