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Regulation of B lymphocyte development by histone H2A deubiquitinase BAP1 (Bap1KO_RNA-Seq)

ABSTRACT: BAP1 is a deubiquitinase (DUB) of the Ubiquitin C-terminal Hydrolase (UCH) family that regulates gene expression and other cellular processes, via deubiquitination of histone H2AK119ub and other substrates. BAP1 is an important tumour suppressor in human, expressed and functional across many cell-types and tissues, including those of the immune system. B lymphocytes are the mediators of humoral immune response, however the role of BAP1 in B cell development and physiology remains poorly understood. Here we characterize a mouse line with a selective deletion of BAP1 within the B cell lineage (Bap1fl/fl mb1-Cre) and establish a cell intrinsic role of BAP1 in the regulation of B cell development. We demonstrate a depletion of large pre-B cells, transitional B cells, and mature B cells in Bap1fl/fl mb1-Cre mice. We characterize broad transcriptional changes in BAP1-deficient pre-B cells, map BAP1 binding across the genome, and analyze the effects of BAP1-loss on histone H2AK119ub levels and distribution. Overall, our work establishes a cell intrinsic role of BAP1 in B lymphocyte development, and suggests its contribution to the regulation of the transcriptional programs of cell cycle progression, via the deubiquitination of histone H2AK119ub.

ORGANISM(S): Mus musculus

PROVIDER: GSE162084 | GEO | 2021/03/29

REPOSITORIES: GEO

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Regulation of B lymphocyte development by histone H2A deubiquitinase BAP1 (BAP1_ChIP-Seq)

Project description:BAP1 is a deubiquitinase (DUB) of the Ubiquitin C-terminal Hydrolase (UCH) family that regulates gene expression and other cellular processes, via deubiquitination of histone H2AK119ub and other substrates. BAP1 is an important tumour suppressor in human, expressed and functional across many cell-types and tissues, including those of the immune system. B lymphocytes are the mediators of humoral immune response, however the role of BAP1 in B cell development and physiology remains poorly understood. Here we characterize a mouse line with a selective deletion of BAP1 within the B cell lineage (Bap1fl/fl mb1-Cre) and establish a cell intrinsic role of BAP1 in the regulation of B cell development. We demonstrate a depletion of large pre-B cells, transitional B cells, and mature B cells in Bap1fl/fl mb1-Cre mice. We characterize broad transcriptional changes in BAP1-deficient pre-B cells, map BAP1 binding across the genome, and analyze the effects of BAP1-loss on histone H2AK119ub levels and distribution. Overall, our work establishes a cell intrinsic role of BAP1 in B lymphocyte development, and suggests its contribution to the regulation of the transcriptional programs of cell cycle progression, via the deubiquitination of histone H2AK119ub.

2021-03-29 | GSE162083 | GEO

B-cell Intrinsic Regulation of Antibody Mediated Immunity by Histone H2A Deubiquitinase BAP1 [ChIP-seq]

Project description:BAP1 is a deubiquitinase (DUB) of the Ubiquitin C-terminal Hydrolase (UCH) family that regulates gene expression and other cellular processes, through its direct catalytic activity on the repressive epigenetic mark histone H2AK119ub, as well as several other substrates. BAP1 is also a highly important tumor suppressor, expressed and functional across many cell types and tissues. In recent work, we demonstrated a cell intrinsic role of BAP1 in the B cell lineage development in murine bone marrow, however the role of BAP1 in the regulation of B cell mediated humoral immune response has not been previously explored. In the current study, we demonstrate that a B-cell intrinsic loss of BAP1 function in activated B cells in the Bap1fl/fl Cγ1-cre murine model results in a severe defect in antibody production, with altered dynamics of germinal centre B cell, memory B cell, and plasma cell numbers. At the cellular and molecular level, BAP1 was dispensable for B cell immunoglobulin class switching but resulted in an impaired proliferation of activated B cells, with genome-wide dysregulation in histone H2AK119ub levels and gene expression. In summary, our study establishes the B-cell intrinsic role of BAP1 in antibody mediated immune response and indicates its central role in the regulation of the genome-wide landscapes of histone H2AK119ub and downstream transcriptional programs of B cell activation and humoral immunity.

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B-cell Intrinsic Regulation of Antibody Mediated Immunity by Histone H2A Deubiquitinase BAP1 [RNA-seq]

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The epigenetic regulator BAP1 is required before birth for differentiation and maintenance of the postnatal enteric nervous system in mice.

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Project description:ASXL1 is the obligate regulatory subunit of a deubiquitinase complex whose catalytic subunit is BAP1. Heterozygous mutations of ASXL1 that result in premature truncations are frequent in myeloid leukemias and Bohring-Opitz syndrome. Here, we demonstrate that truncated ASXL1 proteins confer enhanced activity on the ASXL1-BAP1 complex. Stable expression of truncated, hyperactive ASXL1-BAP1 complexes in a hematopoietic precursor cell line resulted in global erasure of H2AK119Ub, striking depletion of H3K27me3, selective upregulation of a subset of genes whose promoters bore both H2AK119Ub and H3K4me3, and spontaneous differentiation to the mast cell lineage. These outcomes required the catalytic activity of BAP1, indicating these events were downstream consequences of H2AK119Ub erasure. In bone marrow precursors, truncated ASXL1-BAP1 expression cooperated with TET2 loss-of-function to increase differentiation to the myeloid lineage in vivo. We propose that pathological ASXL1 mutations confer gain-of-function on the ASXL-BAP1 complex. ChIP-Seq for H2AK119Ub, H3K4me3, H3K27me3 on EML cells. RNA-Seq on EML cells expressing ASXL1(1-479)+BAP1 and control.

2015-03-11 | E-GEOD-65555 | biostudies-arrayexpress

Pervasive Roles of Ubiquitination in Orchestrating the Deubiquitinase Activity and Function of the BAP1/ASXL2 Tumor Suppressor Complex

Project description:The tumor suppressor and deubiquitinase (DUB) BAP1 regulates chromatin-associated processes and is frequently mutated in various malignancies. BAP1 and its drosophila orthologue Calypso assemble DUB complexes with ASXL-1, -2, -3 paralogues and ASX respectively, and these cofactors are required for stimulating their DUB activity. However how the DUB activity of BAP1 is regulated remains largely unknown. Here we show that BAP1 promotes monoubiquitination of ASXLs on the ASXM/DEUBAD domain. ASXL2 monoubiquitination promotes its stability or proteasomal degradation, stimulates BAP1 DUB activity and is required for mammalian cell proliferation. Monoubiquitination of ASXL2 is directly catalyzed by UBE2E family of ubiquitin conjugating enzymes and is regulated by deubiquitination. Monoubiquitination of ASX is regulated by Calypso and is required for drosophila development. We further revealed a switch mechanism that tightly regulate BAP1 function, as a monoubiquitination of BAP1 UCH domain is mutually exclusive with ASXL2 monoubiquitination, thus ensuring highly coordinated DUB-mediated signaling.

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Rhythmicity of Intestinal IgA Responses Confers Oscillatory Commensal Microbiota Mutualism [1]

Project description:IgA+ Plasma Cells were sort-purified from the small intestinal lamina prorpia of mice with a B cell lineage-intrinsic deletion of Arntl (Mb1 Cre+/- x Arntl fl/fl) or Cre negative littermate controls (also deisgnated WT and KO), at two Zeitgeber time points (ZT0 and ZT12). RNA extracted from these samples was subjected to bulk RNA seq to identify time of day differences and to compare role of Arntl expression in this context.

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Transcriptional profiling of naïve and in vitro activated B cells from WT and DOT1L KO mice

Project description:We studied the role of the histone methyltransferase DOT1L in B cell development and differentiation. Here we generated RNA-seq data naive B cells from (WT) MB1+/-;Dot1L+/+ and Dot1L KO (MB1+/-;Dot1Lfl/fl) mice. This data was to define tissue specific expression signatures and it was compared with H3K79me2 ChIP-seq data from the same subsets.

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Project description:The CCR4-NOT complex, bearing poly(A) deadenylation activity, is a highly conserved regulator that is involved in biological control; however its action mechanisms and physiological targets remain unclear. Using genetic deletion of the CNOT3 subunit of this complex in early B cell progenitors, we show that CNOT3 plays a critical role in pro- to pre-B cell transition. CNOT3 participated in controlling germline transcription, compaction of the immunoglobulin heavy chain (Igh) locus, and Igh rearrangement, and in destabilizing tumor suppressor p53 mRNA. Moreover, by genetic ablation of p53 or introduction of pre-rearranged Igh transgene, the B cell developmental defect in the Cnot3 knockout background could be partly rescued, suggesting that CCR4-NOT complex exerts critical control in B cell differentiation processes by co-utilizing transcriptional and post-transcriptional mechanisms. Pro-B cells mRNA profiles of Mb1(cre/+) and Cnot3(fl/fl)Mb1(cre/+) mice were generated by deep sequencing using Illumina HiSeq 1500

2015-07-23 | E-GEOD-64455 | biostudies-arrayexpress

Bap1 loss results in EZH2 dependent transformation

Project description:BAP1 and ASXL1 interact to form a polycomb deubiquitinase complex that removes monoubiquitin from histone H2A lysine 119 (H2AK119Ub). However, BAP1 and ASXL1 are mutated in distinct cancer types, consistent with independent roles in regulating epigenetic state and malignant transformation. Here we demonstrate that Bap1 loss results in increased trimethylated histone H3 lysine 27 (H3K27me3), elevated Ezh2 expression, and enhanced repression of Polycomb Repressive Complex 2 (PRC2) targets. These findings contrast with the reduction in H3K27me3 seen with Asxl1 loss. Conditional deletion of Bap1 and Ezh2 in vivo abrogates the myeloid progenitor expansion induced by Bap1 loss alone.

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