JMJD1C-mediated epigenetic control of HIT antibody production Free

Heparin-induced thrombocytopenia (HIT) is a common drug-induced immune disorder that occurs in a subset of heparin-treated patients. Immune complexes comprising heparin, platelet factor 4 (PF4), and PF4/heparin-reactive antibodies are central to its pathogenesis. However, the role of epigenetic modification in HIT remains unexplored. JMJD1C is a member of the lysine-specific histone demethylase 3 subfamily, a group of epigenetic regulators that modify chromatin structure and influence gene expression. It has been shown to play a critical role in maintaining the self-renewal capacity of both normal hematopoietic stem cells and leukemia stem cells. To explore the impact of epigenetic modification in HIT, we studied the role of JMJD1C in the production of PF4/heparin-specific antibodies. We generated B–cell–specific Jmjd1c knockout mice by crossing Jmjd1c^flox/flox mice with B-cell-specific Mb1-Cre transgenic mice. JMJD1C was found to be consistently expressed throughout B-cell development. While its deletion did not affect overall B-cell development, it altered basal antibody production and led to a shift in IgG isotype distribution. Moreover, autoantibody array analysis revealed that JMJD1C deficiency enhanced the production of self-reactive antibodies associated with systemic autoimmune responses, underscoring a critical role for JMJD1C in maintaining B-cell immune tolerance. Significantly, JMJD1C deficiency promoted the production of PF4/heparin-specific, platelet-activating antibodies, a hallmark of pathogenic human HIT antibodies.

JMJD1C-deficient B cells exhibited heightened antigen responsiveness, as evidenced by increased B-cell receptor (BCR)-induced upregulation of CD86, a canonical marker of B cell activation, and enhanced proliferation. Transcriptomic analysis (RNA-Seq) revealed upregulation of pathways related to BCR signaling, NF-κB activation, cell cycle progression, and proteasome function, aligning with the observed hyperresponsive phenotype. Chromatin profiling by CUT&Tag-Seq revealed that JMJD1C deficiency led to increased H3K36me1 deposition, a histone mark associated with active chromatin and transcription, at gene promoters and termini of B cell receptor signaling genes, NF-κB pathway targets, and cell cycle–related genes following anti-IgM stimulation. These findings highlight JMJD1C as a critical epigenetic regulator of PF4/heparin-specific antibody production and suggest that its loss drives B-cell hyperactivation through transcriptional dysregulation.

These findings reveal a potential novel epigenetic mechanism underlying HIT pathogenesis, wherein JMJD1C-mediated histone H3K36me1 regulation modulates BCR signaling and NF-κB activation, thereby controlling the production of PF4/heparin-specific antibodies. Our study provides the first evidence linking epigenetic regulation to HIT, offering new insights into its pathophysiology.