Conserved role of hnRNPL in alternative splicing of epigenetic modifiers enables B cell activation

The multifunctional RNA-binding protein hnRNPL has been implicated in antibody class switching but its broader function in B cells is unknown. Here, we show that hnRNPL is essential for B cell activation, and thereby germinal center and antibody responses. Upon activation, hnRNPL-deficient B cells show proliferation defects and increased apoptosis. The comparative analysis of RNA-seq data from B cells and another 8 hnRNPL-depleted cell types reveals a common function in the Myc and E2F transcriptional programs required for proliferation, likely borne out of a large alternative splicing change affecting multiple transcription regulators. Notably, while individual gene expression changes were cell type specific, several alternative splicing events affecting histone modifiers like SIRT1, KDM6A, and NSD2, were conserved across cell types, which could contribute to gene expression changes upon hnRNPL loss. SIRT1 reduction due to alternative splicing, and other transcriptional changes suggested mitochondrial defects in hnRNPL-deficient B cells. We confirmed dysfunctional mitochondria and ROS overproduction, which could explain the B cell activation defect. Thus, hnRNPL is essential for the resting to activated B cell transition by regulating transcriptional programs, most likely by splicing regulation affecting several histone modifiers.