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

Nianwei Lin; Kung-Yen Chang; Zhonghan Li; Keith Gates; Zacharia A Rana; Jason Dang; Danhua Zhang; Tianxu Han; Chao-Shun Yang; Thomas J Cunningham; Steven R Head; Gregg Duester; P Duc Si Dong; Tariq M Rana

doi:10.1016/j.molcel.2014.01.021

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.

Authors

Affiliations

¹ Program for RNA Biology, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
² Program for Genetic Disease, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
³ Program for Development and Aging, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
⁴ The Scripps Research Institute, Microarray and NGS Core Facility, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
⁵ Program for RNA Biology, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Department of Pediatrics, Rady Children's Hospital San Diego and University of California San Diego, La Jolla, CA 92093, USA; Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: trana@sanfordburnham.org.

Abstract

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding