The long noncoding RNA HOTAIRM1 contributes to neuronal differentiation by regulating Neurogenin 2 expression

Neurons derive from neural progenitor cells whose differentiation occurs in two distinct steps, each one involving specific regulatory cascades. The initial production of neuronal precursors, cells already committed to a neuronal fate, is followed by the formation of differentiated cell types that acquire and maintain their identity. The molecular mechanisms underlying these timely-regulated steps are object of intense studies. A prime role in this process is played by proneural genes, regarded as key regulators of neurogenesis. They function by activating neuronal differentiation gene cascade, inhibiting glial cell fates and regulating cell cycle. The proneural transcription factor NEUROGENIN 2 (NEUROG2) is pivotal in the decision between stem cell self-renewal and differentiation. NEUROG2 expression is tightly regulated during differentiation and even subtle alterations of NEUROG2 levels could affect cell fate. NEUROG2 is activated in neuronal precursors to be repressed in post-mitotic cells through a still unknown mechanism. We identified a role in this process for the long noncoding RNA HOTAIRM1, so far described as a regulator of the HOXA genes. We characterized the neuronal isoform of this RNA and found that the nuclear counterpart controls NEUROG2 expression at the epigenetic