An evolutionarily conserved long noncoding RNA TUNA controls pluripotency and neural lineage commitment

Mol Cell. 2014 Mar 20;53(6):1005-19. doi: 10.1016/j.molcel.2014.01.021. Epub 2014 Feb 13.


Here, we generated a genome-scale shRNA library targeting long intergenic noncoding RNAs (lincRNAs) in the mouse. We performed an unbiased loss-of-function study in mouse embryonic stem cells (mESCs) and identified 20 lincRNAs involved in the maintenance of pluripotency. Among these, TUNA (Tcl1 Upstream Neuron-Associated lincRNA, or megamind) was required for pluripotency and formed a complex with three RNA-binding proteins (RBPs). The TUNA-RBP complex was detected at the promoters of Nanog, Sox2, and Fgf4, and knockdown of TUNA or the individual RBPs inhibited neural differentiation of mESCs. TUNA showed striking evolutionary conservation of both sequence- and CNS-restricted expression in vertebrates. Accordingly, knockdown of tuna in zebrafish caused impaired locomotor function, and TUNA expression in the brains of Huntington's disease patients was significantly associated with disease grade. Our results suggest that the lincRNA TUNA plays a vital role in pluripotency and neural differentiation of ESCs and is associated with neurological function of adult vertebrates.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Biological Evolution
  • Cell Differentiation
  • Conserved Sequence
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism
  • Fibroblast Growth Factor 4 / genetics
  • Fibroblast Growth Factor 4 / metabolism
  • Gene Expression Regulation, Developmental*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Huntington Disease / genetics*
  • Huntington Disease / metabolism
  • Huntington Disease / pathology
  • Mice
  • Molecular Sequence Data
  • Motor Activity
  • Nanog Homeobox Protein
  • Neurons / cytology
  • Neurons / metabolism*
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / metabolism*
  • Promoter Regions, Genetic
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism
  • Sequence Homology, Amino Acid
  • Severity of Illness Index
  • Signal Transduction
  • Zebrafish / genetics*
  • Zebrafish / growth & development
  • Zebrafish / metabolism


  • Fgf4 protein, mouse
  • Fibroblast Growth Factor 4
  • Homeodomain Proteins
  • Nanog Homeobox Protein
  • Nanog protein, mouse
  • RNA, Long Noncoding
  • RNA-Binding Proteins
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse

Associated data

  • GEO/GSE46730