Rea, JessicaMenci, ValentinaTollis, PaoloSantini, TizianaArmaos, Alexandros, 1989-Garone, Maria GiovannaIberite, FedericaCipriano, AndreaTartaglia, Gian GaetanoRosa, AlessandroBallarino, MonicaLaneve, PietroCaffarelli, Elisa2020-10-192020-10-192020Rea J, Menci V, Tollis P, Santini T, Armaos A, Garone MG, Iberite F, Cipriano A, Tartaglia GG, Rosa A, Ballarino M, Laneve P, Caffarelli E. HOTAIRM1 regulates neuronal differentiation by modulating NEUROGENIN 2 and the downstream neurogenic cascade. Cell Death Dis. 2020; 11(7):527. DOI: 10.1038/s41419-020-02738-w2041-4889http://hdl.handle.net/10230/45503Neuronal 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. Herein, we identify the long noncoding RNA HOTAIRM1 (HOXA Transcript Antisense RNA, Myeloid-Specific 1) as a new player in neuronal differentiation. We demonstrate that the neuronal-enriched HOTAIRM1 isoform epigenetically controls the expression of the proneural transcription factor NEUROGENIN 2 that is key to neuronal fate commitment and critical for brain development. We also show that HOTAIRM1 activity impacts on NEUROGENIN 2 downstream regulatory cascade, thus contributing to the achievement of proper neuronal differentiation timing. Finally, we identify the RNA-binding proteins HNRNPK and FUS as regulators of HOTAIRM1 biogenesis and metabolism. Our findings uncover a new regulatory layer underlying NEUROGENIN 2 transitory expression in neuronal differentiation and reveal a previously unidentified function for the neuronal-induced long noncoding RNA HOTAIRM1.application/pdfeng© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41419-020-02738-wDifferentiationGene silencingLong non-coding RNAsNeurogenesisProteomicsinfo:eu-repo/semantics/openAccess