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155 Epigenetic Control of B Cell Autoimmunity By Jmjd1c

Program: Oral and Poster Abstracts
Type: Oral
Session: 203. Lymphocytes and Acquired or Congenital Immunodeficiency Disorders: Decoding the Complex Landscape of Human Immunity: Insights From Genetic Mutations to Cellular Heterogeneity
Hematology Disease Topics & Pathways:
Research, Fundamental Science
Saturday, December 9, 2023: 3:00 PM

Yongguang Zhang, PhD1*, Mei Yu, PhD1*, Yongwei Zheng, PhD1*, Yuhong Chen1*, Jesus Izaguirre-Carbonell2*, Nan Zhu, PhD3, Renren Wen, PhD1,4 and Demin Wang, PhD4,5

1Versiti Blood Research Institute, Milwaukee, WI
2Blood Research Institute, Versiti Inc., Milwaukee, WI
3Versiti Blood Research Institute Milwaukee, Milwaukee, WI
4Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
5The Blood Research Institute, Milwaukee, WI

Emerging evidence underscores the importance of epigenetic modifications in controlling B-cell development and function. While Jmjd1c, a member of the lysine-specific histone demethylase 3 subfamily, is known to regulate the self-renewal of normal hematopoietic stem cells and leukemia stem cells, its impact on B cell biology is unknown. To explore Jmjd1c's role in B cells, we developed B-cell-specific Jmjd1c-deficient mice through crossbreeding Jmjd1c "floxed" mice with B cell-specific Mb1-Cre mice. The absence of Jmjd1c did not impact B-cell development, but it did lead to significant alterations in basal B cell antibody production. Specifically, we observed skewed isotypes from IgG2c and IgG3 to IgG1 and IgG2b. Additionally, Jmjd1c deficiency affected antigen-specific immune responses upon T-dependent and T-independent antigen challenges, implying a crucial role of Jmjd1c in B cell function. Furthermore, auto-antibody array assays revealed increased self-reactive antibody production in Jmjd1c-deficient animals, indicating the role of Jmjd1c in regulating self-reactive B cells. At a cellular level, Jmjd1c-deficient B cells showed elevated expression of CD86, a canonical marker of B cell activation. Moreover, these B cells exhibited increased BCR-induced cell proliferation, suggesting hyperactivity to antigens, including self-antigens. Notably, Jmjd1c deficiency induced systemic autoimmune disorder in a BM12-induced systemic lupus erythematosus (SLE) animal model, resulting in amplified auto-antibody production and CD86 expression.

To investigate the underlying molecular mechanisms, RNA sequencing analysis demonstrated upregulation of B cell receptor signaling related genes, NF-κB pathway signature genes, and cell cycle-related genes in Jmjd1c-deficient B cells upon anti-IgM stimulation, consistent with their hyperresponsiveness. Of particular interest, we observed upregulation of genes encoding the 26S proteasome complex, a pivotal regulator of diverse cellular processes including NF-κB pathway activation and self-antigen presentation. To explore the epigenetic aspect of these genes, we employed CUT&Tag sequencing and found that Jmjd1c deficiency correlated with increased levels of H3K36me1, a marker of active chromatin and gene transcription. Moreover, the H3K36me1 levels of B cell receptor signaling related genes, NF-κB pathway signature genes, and cell cycle-related genes were significantly augmented in Jmjd1c-deficient B cells upon anti-IgM stimulation. Notably, 26S proteasome subunit genes that were upregulated in Jmjd1c-deficient B cells exhibited higher H3K36me1 modification at the promoter regions.

Collectively, our study provides valuable insights into the epigenetic control of B cell autoimmunity through the regulation of H3K36 mono-methylation by Jmjd1c. This mechanism plays a critical role in B cell activation and function, including the regulation of key genes such as those encoding the 26S proteasome complex.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH