2'-O-Methylated ncRNA condensates form a recombination center for IgH synapsis

Abstract

How fibrillarin (FBL), an RNA 2'-O-methyltransferase, regulates antibody diversification remains unclear. This study demonstrated that FBL promotes switch (S)-S DNA synapsis at the IgH locus during class switch recombination (CSR), without affecting DNA cleavage. Both RNA-binding and catalytic activities of FBL were essential for CSR. Moreover, MED19 supported DNA cleavage and synapsis by regulating snoRNAs that guide 2'-O-methylation. Mechanistically, FBL methylated -germline transcripts (-GLTs), cis-acting noncoding RNAs forming nuclear condensates harboring machinery for RNA processing, RNP remodeling, and chromatin dynamics. FBL-mediated 2'-O-methylation governed condensate protein composition. FBL suppression aberrantly enriched nucleolar proteins, including WDR74. Crucially, low WDR74 expression in B cells promoted - and -GLT condensate fusion, thereby enhancing S-S synapsis, CSR, and IgH/c-Myc translocation, potentially contributing to poor myeloma prognosis. Altogether, our findings revealed that RNA 2'-O-methylation dictates GLT condensate composition and fusion dynamics to establish a recombination center, driving genomic DNA synapsis in B cells.