Mechanisms of Long Non-coding RNAs in Mammalian Nervous System Development, Plasticity, Disease, and Evolution
2015; Cell Press; Volume: 88; Issue: 5 Linguagem: Inglês
10.1016/j.neuron.2015.09.045
ISSN1097-4199
AutoresJames Briggs, Ernst J. Wolvetang, John S. Mattick, John L. Rinn, Guy Barry,
Tópico(s)RNA modifications and cancer
ResumoOnly relatively recently has it become clear that mammalian genomes encode tens of thousands of long non-coding RNAs (lncRNAs). A striking 40% of these are expressed specifically in the brain, where they show precisely regulated temporal and spatial expression patterns. This begs the question, what is the functional role of these many lncRNA transcripts in the brain? Here we canvass a growing number of mechanistic studies that have elucidated central roles for lncRNAs in the regulation of nervous system development and function. We also survey studies indicating that neurological and psychiatric disorders may ensue when these mechanisms break down. Finally, we synthesize these insights with evidence from comparative genomics to argue that lncRNAs may have played important roles in brain evolution, by virtue of their abundant sequence innovation in mammals and plausible mechanistic connections to the adaptive processes that occurred recently in the primate and human lineages. Only relatively recently has it become clear that mammalian genomes encode tens of thousands of long non-coding RNAs (lncRNAs). A striking 40% of these are expressed specifically in the brain, where they show precisely regulated temporal and spatial expression patterns. This begs the question, what is the functional role of these many lncRNA transcripts in the brain? Here we canvass a growing number of mechanistic studies that have elucidated central roles for lncRNAs in the regulation of nervous system development and function. We also survey studies indicating that neurological and psychiatric disorders may ensue when these mechanisms break down. Finally, we synthesize these insights with evidence from comparative genomics to argue that lncRNAs may have played important roles in brain evolution, by virtue of their abundant sequence innovation in mammals and plausible mechanistic connections to the adaptive processes that occurred recently in the primate and human lineages. Advances in genome sequencing technologies during the last decade have enabled an unprecedented scale of transcript discovery. One of the key results has been the finding that non-protein-coding transcripts dominate the transcriptional output of mammalian genomes (Birney et al., 2007Birney E. Stamatoyannopoulos J.A. Dutta A. Guigó R. Gingeras T.R. Margulies E.H. Weng Z. Snyder M. Dermitzakis E.T. Thurman R.E. et al.ENCODE Project ConsortiumNISC Comparative Sequencing ProgramBaylor College of Medicine Human Genome Sequencing CenterWashington University Genome Sequencing CenterBroad InstituteChildren’s Hospital Oakland Research InstituteIdentification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project.Nature. 2007; 447: 799-816Crossref PubMed Scopus (3044) Google Scholar, Carninci et al., 2005Carninci P. Kasukawa T. Katayama S. Gough J. Frith M.C. Maeda N. Oyama R. Ravasi T. Lenhard B. 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Specific expression of long noncoding RNAs in the mouse brain.Proc. Natl. Acad. Sci. USA. 2008; 105: 716-721Crossref PubMed Scopus (581) Google Scholar). In fact, it was recently shown that lncRNAs provide more information about cell type identity during mammalian cortical development than protein-coding genes (Molyneaux et al., 2015Molyneaux B.J. Goff L.A. Brettler A.C. Chen H.H. Brown J.R. Hrvatin S. Rinn J.L. Arlotta P. DeCoN: genome-wide analysis of in vivo transcriptional dynamics during pyramidal neuron fate selection in neocortex.Neuron. 2015; 85: 275-288Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). These dynamics and region-specific expression patterns are coordinated by cell-type-specific or activity-dependent transcription factors and canonical changes in chromatin state at lncRNA loci (Kim et al., 2010bKim T.K. Hemberg M. Gray J.M. Costa A.M. Bear D.M. Wu J. Harmin D.A. Laptewicz M. Barbara-Haley K. 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Transcription of two long noncoding RNAs mediates mating-type control of gametogenesis in budding yeast.Cell. 2012; 150: 1170-1181Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar) as nascent transcripts. In contrast, trans-acting lncRNAs bind to and impact the expression of target genes throughout the genome, which are often distant to the lncRNA locus (Chu et al., 2011Chu C. Qu K. Zhong F.L. Artandi S.E. Chang H.Y. Genomic maps of long noncoding RNA occupancy reveal principles of RNA-chromatin interactions.Mol. Cell. 2011; 44: 667-678Abstract Full Text Full Text PDF PubMed Scopus (473) Google Scholar, Johnsson et al., 2013Johnsson P. Ackley A. Vidarsdottir L. Lui W.O. Corcoran M. Grandér D. Morris K.V. A pseudogene long-noncoding-RNA network regulates PTEN transcription and translation in human cells.Nat. Struct. Mol. Biol. 2013; 20: 440-446Crossref PubMed Scopus (182) Google Scholar, Vance et al., 2014Vance K.W. Sansom S.N. Lee S. Chalei V. Kong L. Cooper S.E. 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