AKNA drives neural stem cell fate transition through differential localization and coordinating the modulation of chromatin from H3K27me3 to H3K27ac

Neuronal stem cells (NSCs) play pivotal role in adult neurogenesis, however, detail mechanisms of obtaining pluripotency or undergoing differentiation remain unknown. Herein, how AT-hook protein AKNA regulates pluripotency and stemness in neuroblastoma cells is demonstrated by gene knockdown, immunofluorescence, chromatin immunoprecipitation (ChIP), localization of AKNA, signaling interactions and transcriptional activity. AKNA was abundant and mostly nuclear during induction of pluripotency and its knockdown reduced stemness, even in presence of other pluripotency factors, including OCT4 and SOX2. During the course of induction of differentiation, AKNA remain localized in the cytosol, essential for regulated differentiation. Cytosolic retention of AKNA is possibly driven by FAK signaling. In the nucleus, AKNA promotes KDM6B demethylase for H3K27me3 demethylation to H3K27, and subsequently promotes CBP/p300 to acetylate H3K27 to H3K27ac deposition on promoter region of respective genes to trigger their transcription. Data obtained from knockdown and overexpression of AKNA and KDM6B further reinforce its importance that, they physically interact to drive pluripotency and stemness. These findings establish AKNA as a critical regulator for NSCs fate determination in association with epigenetic modifiers and signaling pathway, offering potential targets for neuroblastoma therapies and regenerative medicines for neurodegenerative diseases.