Epigenetic remodeling is required during B cell differentiation. However, little is known about the direct functions of epigenetic enzymes in Ab-secreting cells (ASC) in vivo. In this study, we examined ASC differentiation independent of T cell help and germinal center reactions using mice with inducible or B cell–specific deletions of Ezh2. Following stimulation with influenza virus or LPS, Ezh2-deficient ASC poorly proliferated and inappropriately maintained expression of inflammatory pathways, B cell–lineage transcription factors, and Blimp-1–repressed genes, leading to fewer and less functional ASC. In the absence of EZH2, genes that normally gained histone H3 lysine 27 trimethylation were dysregulated and exhibited increased chromatin accessibility. Furthermore, EZH2 was also required for maximal Ab secretion by ASC, in part due to reduced mitochondrial respiration, impaired glucose metabolism, and poor expression of the unfolded-protein response pathway. Together, these data demonstrate that EZH2 is essential in facilitating epigenetic changes that regulate ASC fate, function, and metabolism.

Systemic sclerosis (SSc) is a multisystem fibrotic and autoimmune disease. Both genetic and epigenetic elements mediate SSc pathophysiology. This review summarizes the role of one epigenetic element, known as microRNAs (miRNAs), involved in different signaling pathways of SSc pathogenesis. The expression of key components in transforming growth factor-β (TGF-β) signaling pathway has been found to be regulated by miRNAs both upstream and downstream of TGF-β. We are specifically interested in the pathway components upstream of TGF-β, while miRNAs in other signaling pathways have not been extensively studied. The emerging role of miRNAs in vasculopathy of SSc suggests a promising new direction for future investigation. Elucidation of the regulatory role of miRNAs in the expression of signaling factors may facilitate the discovery of novel biomarkers in SSc and improve the understanding and treatment of this disease.

Objective: METTL3, an m6A methyltransferase, enhances germinal center responses. This study explores its role in lupus B cells and its impact on B-cell activation. Methods: METTL3 and m6A levels in B cells from systemic lupus erythematosus (SLE) patients and lupus-prone mice were analyzed using m6A dot blot, RT-qPCR, western blotting, and flow cytometry. B-cell activation and differentiation were induced with lipopolysaccharide (LPS). The effects of METTL3 overexpression or inhibition on B-cell maturation were assessed in vivo . In Raji B cells, METTL3 and PAX5 knockdowns were performed to examine their regulatory relationship. EMSA and dual-luciferase assays confirmed PAX5 binding to the METTL3 promoter, while RIP and actinomycin D assays evaluated METTL3’s interaction with PAX5 mRNA. MeRIP-seq profiled m6A modifications across B-cell subsets. Results: METTL3 expression and m6A levels were significantly elevated in B cells from SLE patients, with METTL3 levels positively correlating with disease activity. Elevated m6A and METTL3 levels were observed in both naïve and activated B cells but decreased markedly during differentiation into ASCs, both in vivo and in vitro . MeRIP-seq analysis identified distinct m6A methylation patterns among B-cell subsets, particularly in key transcription factors critical for B-cell activation and differentiation. METTL3 facilitated pre-B cell development in bone marrow and maintained the balance of splenic B-cell subsets in mice. Furthermore, METTL3 preserved B-cell identity and enhanced activation. Mechanistically, METTL3 bound to PAX5 mRNA, stabilizing it via m6A modification and promoting PAX5 expression. In turn, PAX5 directly bound to the METTL3 promoter, driving its expression. Conclusion: The elevated expression of METTL3 in lupus B cells is linked to the maintenance of autoreactive B-cell hyperresponsiveness, contributing to the pathogenesis of SLE. The reciprocal regulation between METTL3 and PAX5 highlights a critical mechanism underlying B-cell activation and persistence in autoimmune conditions like lupus.