HOTAIRM1 regulates neuronal differentiation by controlling NEUROGENIN 2 and the downstream neurogenic cascade

Neuronal differentiation is a timely and spatially regulated process, relying on precisely orchestrated gene expression control. The sequential activation/repression of genes driving cell fate specification is achieved by complex regulatory networks, where transcription factors and noncoding RNAs work in a coordinated manner. Here, we provide the molecular, functional and mechanistic characterization of the long noncoding RNA HOTAIRM1 (HOXA Transcript Antisense RNA, Myeloid-Specific 1) as a new player in neuronal differentiation. At the molecular level, we describe HOTAIRM1 neuronal isoform and identify the RNA-binding proteins HNRNPK and FUS as regulators of its biogenesis and metabolism. Functionally, we discover that HOTAIRM1 controls the expression of the proneural transcription factor NEUROGENIN 2, that is key to neuronal fate commitment and critical for brain development. We demonstrate that, during neuronal differentiation, nuclear HOTAIRM1 controls the transitory expression of NEUROGENIN 2. Mechanistically, HOTAIRM1 acts as an epigenetic regulator that, recruiting the repressive complex PRC2, contributes to limit the time-window of NEUROGENIN 2 expression. Remarkably, HOTAIRM1 also controls NEUROGENIN 2 downstream regulatory cascade contributing to the achievement of proper neuronal differentiation timing.