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

Cell Death Dis. 2020 Jul 13;11(7):527. doi: 10.1038/s41419-020-02738-w.

Abstract

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. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Differentiation / physiology
  • Cell Line, Tumor
  • Epigenesis, Genetic
  • Gene Silencing
  • Heterogeneous-Nuclear Ribonucleoprotein K / genetics
  • Heterogeneous-Nuclear Ribonucleoprotein K / metabolism
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / cytology*
  • Neurons / metabolism*
  • Proteomics / methods*
  • RNA-Binding Protein FUS / genetics
  • RNA-Binding Protein FUS / metabolism
  • Transcription Factors / metabolism*
  • Transfection

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • FUS protein, human
  • Heterogeneous-Nuclear Ribonucleoprotein K
  • MicroRNAs
  • NEUROG2 protein, human
  • Nerve Tissue Proteins
  • RNA-Binding Protein FUS
  • Transcription Factors
  • long non-coding RNA HOTAIRM1, human
  • HNRNPK protein, human