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Arid2 promotes Follicular B-cell differentiation and antibody responses in vivo

ABSTRACT: SWI/SNF chromatin remodeling complexes, also known as BAF complexes, regulate gene expression during development and differentiation. These complexes exist in distinct variants, including the polybromo-associated BAF (PBAF) complex, defined by the ARID2 core subunit. ARID2 is frequently mutated in B cell leukemias, but its role in normal B cell development remains unknown. Using conditional knockout mice, we show that Arid2 deletion impairs B cell differentiation in vivo. Mb1-Cre–mediated deletion, active in early progenitors, caused a marked reduction of splenic and circulating Follicular B cells, whereas CD19-Cre deletion produced a milder phenotype. These defects were not due to altered proliferation or survival but reflected impaired differentiation potential. Transcriptomic profiling of isolated pro-B, pre-B, and Follicular B cells revealed that Arid2 loss disrupts stage-specific gene expression programs, with cumulative downregulation of B cell receptor signaling and altered lineage-specifying pathways. Functionally, Arid2-deficient mice exhibited impaired germinal center expansion after immunization and reduced IgG antibody production. Together, these findings identify Arid2 as a critical regulator of B cell differentiation and maturation by coordinating transcriptional programs during early lymphopoiesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE307667 | GEO | 2025/09/26

REPOSITORIES: GEO

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Arid2 promotes Follicular B-cell differentiation and antibody responses in vivo

Project description:Arid2 promotes Follicular B-cell differentiation and antibody responses in vivo

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ARID2 promotes clear cell renal cell carcinoma in the absence of functional PBRM1 [ARID2 ChIP-seq]

Project description:Subunits of SWI/SNF chromatin remodeling complexes are frequently mutated in human malignancies. The PBAF complex is composed of multiple subunits, including the putative tumor suppressor proteins PBRM1 (BAF180) and ARID2 (BAF200) that are unique to this SWI/SNF complex. PBRM1 is mutated in various cancers, with a high mutation frequency in clear cell renal cell carcinoma (ccRCC). Here, we integrate RNA-seq, ARID2 and histone mark ChIP-seq, and ATAC-seq data to show that PBAF acts to enhance or repress gene expression depending on the genomic context. At baseline, ARID2 binds to areas of open chromatin at both active enhancers and promoters. Depletion of PBRM1 leads to attenuated and redistributed ARID2 chromatin binding that correlates significantly with gene expression changes. At enhancers, ARID2 binding loss leads to diminishment of the histone mark H3K4me1 and gene downregulation. Alternatively, at a subset of promoters, ARID2 binding loss derepresses gene expression. Interestingly, ARID2, which remains bound to other PBAF subunits after loss of PBRM1, is essential for many of the pro-tumorigenic transcriptional changes observed after loss of PBRM1, whereas other core SWI/SNF components are dispensable. Upon loss of PBRM1, ARID2 positively regulates cancer-related genes and pathways, including the cancer stem cell marker ALDH1A1 and EGF signaling, to stimulate tumor cell growth. Therefore, ARID2 is crucial for maintaining the transformed state of PBRM1-deficient ccRCC cells. In total, this study suggests a novel mechanism of transcriptional control by PBRM1, whereby its loss alters the chromatin distribution of the residual PBAF complex leading to altered transcription that promotes tumorigenesis.

2018-08-14 | GSE102803 | GEO

Conditional deletion of Bcl6 in naive B cells

Project description:Bcl6 germline deletion causes a prominent inflammatory disease, owing to over-expression of Th2 cytokines, and affects the properties of B cells prior to immunization. Therefore we established the B cell-specific Bcl6 deletion mice and analyze the gene expression of naive B cells under physiological conditions. Total RNAs of splenic follicular and marginal zone B cells from Bcl6(flox/flox), Bcl6(+/flox) or Bcl6(+/+) mice heterozygous for mb1-cre were extracted and analysed on Affymetrix microarrays.

2012-09-21 | E-GEOD-28737 | biostudies-arrayexpress

ARID2 promotes clear cell renal cell carcinoma in the absence of functional PBRM1 [microarray]

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ARID2 promotes clear cell renal cell carcinoma in the absence of functional PBRM1 [RNA-seq]

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ARID2 promotes clear cell renal cell carcinoma in the absence of functional PBRM1 [ATAC-seq]

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ARID2 promotes clear cell renal cell carcinoma in the absence of functional PBRM1 [Histone modification native ChIP-seq]

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Disruption of DNA damage response by ARID2 knockout in human hepatocellular carcinoma cells

Project description:Background & Aims: Recent genomic studies have identified frequent mutations of AT-rich interactive domain 2 (ARID2) in hepatocellular carcinoma (HCC), but it is not still understood how ARID2 exhibits tumor suppressor activities. Methods: We established the ARID2 knockout HCC cell lines by using CRISPR/Cas9 system, and investigated the gene expression profiles and biological functions. Results: Bioinformatic analysis indicated that UV-response genes were negatively regulated in the ARID2-KO cells, and they were certainly sensitized to UV irradiation. ARID2 depletion attenuated nucleotide excision repair (NER) of DNA damage sites introduced by exposure to UV as well as chemical compounds known as carcinogens for HCC, benzo[a]pyrene and FeCl3, since XPG could not be accumulated without ARID2. By using large-scale public data sets, we validated that ARID2 knockout could lead to similar molecular changes between in vitro and in vivo, and moreover observed a higher number of somatic mutations in the ARID2-mutated subtypes than that in the ARID2 wild-type across various types of cancers including HCC. Conclusions: We provided evidence that ARID2 knockout could contribute to disruption of NER process through inhibiting the recruitment of XPG, resulting in susceptibility to carcinogens and potential hypermutation. These findings have far-reaching implications for therapeutic targets in cancers harboring ARID2 mutations.

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ARID2 mitigates hepatic steatosis via promoting the ubiquitination of JAK2

Project description:Non-alcoholic fatty liver disease (NAFLD) has become a growing public health problem. However, the complicated pathogenesis of NAFLD contributes to the deficiency of effective clinical treatment. Here, we elucidated that liver-specific loss of Arid2 induced hepatic steatosis and this progression could be exacerbated by HFD. Mechanistic study revealed that ARID2 repressed JAK2-STAT5-PPARγ signaling pathway by promoting the ubiquitination of JAK2, which was mediated by NEDD4L, a novel E3 ligase for JAK2. ChIP assay revealed that ARID2 recruited CARM1 to increase H3R17me2 level at NEDD4L promoter and activated the transcription of NEDD4L. Moreover, inhibition of Jak2 by Fedratinib in liver-specific Arid2 knockout mice alleviated HFD-induced hepatic steatosis. Downregulation of ARID2 and the reverse correlation between ARID2 and JAK2 were also observed in clinical samples. Therefore, our study has revealed an important role of ARID2 in the development of NAFLD and provides a potential therapeutic strategy for NAFLD.

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