JMJD1C-mediated epigenetic control of autoimmunity and HIT antibody production

JMJD1C-deficient B cells were hyperresponsive, characterized by enhanced B-cell receptor (BCR)-induced proliferation. Transcriptomic analysis (RNA-Seq) revealed upregulation of pathways associated with BCR signaling, NF-kB activation, the cell cycle, and systemic lupus erythematosus (SLE). CUT&Tag profiling demonstrated that JMJD1C deficiency increased H3K36me1 modification at gene start sites in these pathways, indicating that epigenetic dysregulation drives B-cell hyperactivation.

Importantly, transcriptional profiling and regulon analysis of B cells from HIT patients showed enrichment of BCR signaling, cell-cycle, NF-κB, and SLE-associated pathways, closely mirroring those in JMJD1C-deficient B cells. Epigenetic analyses further revealed enhanced promoter chromatin accessibility and elevated H3K36me1 deposition at promoter-TSS regions in HIT B cells. Together, these findings establish a strong molecular overlap between JMJD1C deficiency and human HIT B cells and reveal a previously unrecognized epigenetic mechanism underlying HIT pathogenesis.

Our study provides the first evidence linking epigenetic regulation to HIT, offering new insights into its pathophysiology.