title: An evolutionarily conserved long noncoding RNA TUNA controls pluripotency and neural lineage commitment.
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.
authors: Program for RNA Biology, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Nianwei
authors: N
authors: Lin
authors: Program for RNA Biology, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Kung-Yen
authors: KY
authors: Chang
authors: Program for RNA Biology, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Zhonghan
authors: Z
authors: Li
authors: Program for Genetic Disease, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Keith
authors: K
authors: Gates
authors: Program for RNA Biology, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Zacharia A
authors: ZA
authors: Rana
authors: Program for RNA Biology, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Jason
authors: J
authors: Dang
authors: Program for Genetic Disease, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Danhua
authors: D
authors: Zhang
authors: Program for RNA Biology, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Tianxu
authors: T
authors: Han
authors: Program for RNA Biology, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Chao-Shun
authors: CS
authors: Yang
authors: Program for Development and Aging, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Thomas J
authors: TJ
authors: Cunningham
authors: The Scripps Research Institute, Microarray and NGS Core Facility, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Steven R
authors: SR
authors: Head
authors: Program for Development and Aging, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Gregg
authors: G
authors: Duester
authors: Program for Genetic Disease, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: P Duc Si
authors: PD
authors: Dong
authors: 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.
authors: Tariq M
authors: TM
authors: Rana
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005075:Biological Evolution; D002454:Cell Differentiation; D017124:Conserved Sequence; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D051519:Fibroblast Growth Factor 4 / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D009043:Motor Activity; D000071317:Nanog Homeobox Protein; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012720:Severity of Illness Index; D015398:Signal Transduction; D015027:Zebrafish / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism
chemical_list: C496446:Fgf4 protein, mouse; D051519:Fibroblast Growth Factor 4; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D062085:RNA, Long Noncoding; D016601:RNA-Binding Proteins; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse