HNRNPA2B1-mediated m6A modification enhances lncRNA NORHA stability to control granulosa cell functions

NORHA is a pivotal long non-coding RNA (lncRNA) that induces sow follicular atresia triggered by granulosa cell (GC) apoptosis. However, whether it is regulated by N6-methyladenosine (m6A), the most abundant RNA modification, is unclear. Herein, we report that NORHA is a functional target of an m6A reader HNRNPA2B1 in sow GCs (sGCs). We characterized RNA modification sites in NORHA transcript, and showed several RNA modifications such as m6A were enriched on it in sGCs. Mechanistically, HNRNPA2B1 stabilizes NORHA in sGCs by facilitating m6A modification of multiple m6A sites including A261, A441 and A919 by directly interacting with its transcript. Functionally, HNRNPA2B1 restrains 17β-estradiol (E2) synthesis and facilitates cell apoptosis in sGCs through activating the NORHA/FoxO1 axis, then FoxO1 acts as a transcription repressor to restrain the transcription of CYP19A1, a transcript that encoding an enzyme that catalyzes E2 synthesis. Additionally, HNRNPA2B1 mediates METTL3, a major m6A methyltransferase, regulation of m6A modification and functions of NORHA in sGCs. This study highlights an important m6A-dependent regulatory mechanism of lncRNA NORHA expression in sGCs.