The RNA binding protein LIN28A mediates chromatin dynamics during neuronal differentiation

The transition of embryonic stem cells (ESCs) from pluripotency to lineage commitment involves complex regulatory mechanisms, including chromatin dynamics and transcriptional/post- transcriptional processes. These mechanisms often interact within intricate networks that require thorough investigation. In this study, we highlight the critical role of the mouse RNA-binding protein LIN28A in neuronal differentiation. LIN28A mediates RNA-dependent interactions with thePolycomb repressive complex 2 (PRC2), leading to the eviction of PRC2 from chromatin andactivation of a neuronal lineage-specific transcriptional program. Proteomic analyses revealed thatthe LIN28A interactome undergoes substantial remodeling during differentiation, corresponding to changes in LIN28A localization. In undifferentiated ESCs, LIN28A primarily resides in the nucleus,interacting with PRC2 components in an RNA-dependent manner, assisting in chromatin dynamics. The absence of LIN28A results in persistent PRC2 association with chromatin, impairing theexpression of genes critical for neuronal differentiation. Chromatin immunoprecipitationsequencing further confirmed that loss of LIN28A results in preferential PRC2 occupancy at thepromoters of differentiation-associated genes. These findings reveal a novel role of LIN28A inepigenetic remodeling, crucial for proper neuronal differentiation of ESCs.