Regulation of B Lymphocyte Development by Histone H2A Deubiquitinase BAP1

Lin, Yun; Liang, Yue; Wang, HanChen; Tung, Lin Tze; Förster, Michael; Subramani, Poorani Ganesh; Noia, Javier M. Di; Clare, Simon; Langlais, David; Nijnik, Anastasia

doi:10.3389/fimmu.2021.626418

Cited by 9 publications

(28 citation statements)

References 104 publications

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“…To test the role of BAP1 in regulating Schwann cell development and maturation, we developed a Schwann cell specific conditional knockout (cKO) of Bap1 using the Mpz ‐cre driver, which is active in embryonic Schwann cell development at E13.5–14.5 (Feltri et al, 1999). The loxP sites surround exons 6–12 of Bap1 including part of the catalytic UCH domain (Figure 1 a) (Lin et al, 2021). The deletion results in a frameshift 3′ of the deletion, leading to loss of the C‐terminal sequence.…”

Section: Resultsmentioning

confidence: 99%

Modulation of Schwann cell homeostasis by the BAP1 deubiquitinase

Duong

Ramesh

Schneider

et al. 2023

Glia

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Schwann cell programming during myelination involves transcriptional networks that activate gene expression but also repress genes that are active in neural crest/embryonic differentiation of Schwann cells. We previously found that a Schwann cell‐specific deletion of the EED subunit of the Polycomb Repressive Complex (PRC2) led to inappropriate activation of many such genes. Moreover, some of these genes become re‐activated in the pro‐regenerative response of Schwann cells to nerve injury, and we found premature activation of the nerve injury program in a Schwann cell‐specific knockout of Eed. Polycomb‐associated histone modifications include H3K27 trimethylation formed by PRC2 and H2AK119 monoubiquitination (H2AK119ub1), deposited by Polycomb repressive complex 1 (PRC1). We recently found dynamic regulation of H2AK119ub1 in Schwann cell genes after injury. Therefore, we hypothesized that H2AK119 deubiquitination modulates the dynamic polycomb repression of genes involved in Schwann cell maturation. To determine the role of H2AK119 deubiquitination, we generated a Schwann cell‐specific knockout of the H2AK119 deubiquitinase Bap1 (BRCA1‐associated protein). We found that loss of Bap1 causes tomacula formation, decreased axon diameters and eventual loss of myelinated axons. The gene expression changes are accompanied by redistribution of H2AK119ub1 and H3K27me3 modifications to extragenic sites throughout the genome. BAP1 interacts with OGT in the PR‐DUB complex, and our data suggest that the PR‐DUB complex plays a multifunctional role in repression of the injury program. Overall, our results indicate Bap1 is required to restrict the spread of polycomb‐associated histone modifications in Schwann cells and to promote myelin homeostasis in peripheral nerve.

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Section: Resultsmentioning

confidence: 99%

Modulation of Schwann cell homeostasis by the BAP1 deubiquitinase

Duong

Ramesh

Schneider

et al. 2023

Glia

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“…Absolute cell numbers per spleen are presented; all data are from n ≥ 5 mice per group and reproduced in ≥2 independent experiments; bars represent mean ± SEM; statistical analyses used unpaired Student's t ‐test; * p < 0.05, ** p < 0.01. Gating strategies are presented in Figures S1, S2 and were previously described [32, 58, 59]. (d) Total splenic B cells were gated as live CD19 + cells.…”

Section: Resultsmentioning

confidence: 99%

Dysregulation of B lymphocyte development in the SKG mouse model of rheumatoid arthritis

Kim,

Tung,

Jiang

et al. 2023

Immunology

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Rheumatoid arthritis is a chronic and systemic inflammatory disease that affects approximately 1% of the world's population and is characterised by joint inflammation, the destruction of articular cartilage and bone, and many potentially life‐threatening extraarticular manifestations. B lymphocytes play a central role in the pathology of rheumatoid arthritis as the precursors of autoantibody secreting plasma cells, as highly potent antigen‐presenting cells, and as a source of various inflammatory cytokines, however, the effects of rheumatoid arthritis on B lymphocyte development remain poorly understood. Here, we analyse B lymphocyte development in murine models of rheumatoid arthritis, quantifying all the subsets of B cell precursors in the bone marrow and splenic B cells using flow cytometry. We demonstrate a severe reduction in pre‐B cells and immature B cells in the bone marrow of mice with active disease, despite no major effects on the mature naïve B cell numbers. The loss of B cell precursors in the bone marrow of the affected mice was associated with a highly significant reduction in the proportion of Ki67+ cells, indicating impaired cell proliferation, while the viability of the B cell precursors was not significantly affected. We also observed some mobilisation of the B cell precursor cells into the mouse spleen, demonstrated with flow cytometry and pre‐B colony forming units assays. In summary, the current work demonstrates a severe dysregulation in B lymphocyte development in murine rheumatoid arthritis, with possible implications for B cell repertoire formation, tolerance induction, and disease mechanisms.

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“…cell metabolism [37] , cellular differentiation [38,39] , and immune regulation [40,41] . Of the four tumors with BAP1 mutations in our study, two were substitutions and two were truncations.…”

Section: Discussionmentioning

confidence: 99%

The clinical outcome, pathologic spectrum, and genomic landscape of 454 cases of salivary mucoepidermoid carcinoma

Wang¹,

Yan

et al. 2023

Preprint

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Objectives To investigate the clinicopathological and molecular features of salivary mucoepidermoid carcinoma (MEC).Design The clinical features, treatment outcomes, and pathological parameters of 454 MECs were evaluated, and their genomic features were analyzed using whole-exome sequencing and whole-transcriptome sequencing.Results 414 patients were alive without relapse at follow-up, after an average period of 62 months (1–116 months). The disease progressed after initial treatment in 40 patients. The lungs were the most common site of distant metastasis. For classical MECs, histologic gradings of the AFIP, modified Healey, and MSK systems were significantly associated with recurrence and lymph nodal metastasis; these gradings were significantly related to lymph nodal metastasis for the subtypes. Older age, minor salivary gland involvement, clinical symptoms, high TNM stage, high-grade tumor, and improper surgical modality were the main prognostic factors. BAP1 was the most frequently mutated gene in MEC. Mutations in CDKN2A, MET, and TP53 were more frequently found in aggressive tumor phenotypes. MAML2 rearrangement was observed in 42% of patients, and EWSR1 rearrangement in 8%. Specific genetic events (in TP53 and FBXW7) associated with CRTC1–MAML2 fusion might cause MEC progression and might be associated with unfavorable prognosis.Conclusions A complete understanding of the high heterogeneity of MEC in histology and genetics would help in accurate diagnosis and treatment.

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Regulation of B Lymphocyte Development by Histone H2A Deubiquitinase BAP1

Cited by 9 publications

References 104 publications

Modulation of Schwann cell homeostasis by the BAP1 deubiquitinase

Modulation of Schwann cell homeostasis by the BAP1 deubiquitinase

Dysregulation of B lymphocyte development in the SKG mouse model of rheumatoid arthritis

The clinical outcome, pathologic spectrum, and genomic landscape of 454 cases of salivary mucoepidermoid carcinoma

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