review rNA Biology 9:6, 860-870; June 2012; © 2012 Landes Bioscience Involvement of long noncoding RNAs in diseases affecting the central nervous system Chiara Pastori and Claes w ahlestedt* Department of Psychiatry and Behavioral Sciences and Center for Therapeutic innovation; Hussman institute for Human Genomics; University of Miami; Miami, FL USA Keywords: long noncoding RNAs, epigenetics, RNA-binding proteins, RNA-targeting therapies, neurological disorders, brain cancer DNA sequences associated with protein-coding genes have been the primary focus of most genetic analyses of complex human diseases. Although we are rapidly gaining a comprehensive view of the etiology of certain central nervous system disorders, major gaps in our understanding persist. r ecent studies have uncovered that many human genomic sequences are transcribed but not translated, generating an astounding diversity of noncoding r NAs (ncr NAs). This awareness should be taken into account when studying human diseases and may have profound implications on the development of novel biomarkers as well as therapies. Introduction The majority of transcription in humans results in the produc- tion of long non-protein-coding RNAs (lncRNAs), ranging from 200 bp up to several kilobases long. LncRNAs have only recently emerged as a major category of regulatory eukaryotic transcripts and can be classified into groups based on their location within genome. Natural antisense transcripts (NATs) arise from the opposite strand of protein-coding or non protein-coding genes1-7 and can overlap with exons, promoter or other regulatory ele- ments of their cognate genes. Another class originates from the introns, promoters or 3' termini of protein-coding genes.8-10 Finally, long intergenic RNAs (lincRNAs) are transcripts origi- nating from genomic regions outside the boundaries of pro- tein-coding genes.11 Next generation sequencing of the human transcriptome has unearthed tens of thousands of lncRNAs from each class that are transcribed from specific cell and tissue types. As of February 2012, approximately 200 lncRNAs have been functionally annotated in the long noncoding RNA database (www.lncrnadb.com).12 Although relatively few lncRNAs have been functionally characterized, increasing evidence suggests an important role for the thousands of uncharacterized remaining transcripts. LncRNAs can have diverse functions including the ability to modulate transcription, regulate post-transcriptional RNA processing,13 translation,14 DNA methylation and chromatin *Correspondence to: Claes Wahlestedt; Email: cwahlestedt@med.miami.edu Submitted: 02/10/12; Revised: 04/18/12; Accepted: 04/23/12 http://dx.doi.org/10.4161/rna.20482 architecture through local (cis) and long distance (trans) mecha- nisms.15 Through interactions with transcription factors, co-acti- vators and/or repressors, lncRNAs can affect different aspects of gene transcription to form a fine-tuned complex regulatory network. LncRNAs can modulate the activity of transcriptional machinery in cis in two main ways: by directly affecting tran- scription factors and their association with co-regulators16-18 or by orchestrating chromatin-remodeling events.19-21 Perhaps the most prominent mechanism involving lncRNAs is the recruit- ment of chromatin remodeling complexes, e.g., histone methyl- transferases that methylate histones to either activate or repress gene transcription, in specific genomic loci. Interestingly, chro- matin-remodeling proteins do not possess DNA-binding activ- ity, suggesting that specific ncRNAs may be the critical link between these enzymes and the genome. In contrast to cis-acting lncRNAs, some transcripts exert their function by modulating gene expression on genomic loci other than the one from which they originate (trans activity).11,22,23 Altered Expression of lncRNAs in CNS Diseases Central nervous system (CNS) development, synaptic plasticity and the stress response are all tightly linked to epigenetic mecha- nisms that drive gene expression.24 Temporal and spatial expres- sion of lncRNAs appears to be important for proper neurological functioning through the precise regulation of epigenetic events. Many lncRNAs are expressed in the CNS where they have been shown to play fundamental roles.15,25 MALAT-1 is a lncRNA that was originally described as being overexpressed in different metastatic tumors, however it has recently been found to play a role in synapse formation.26 MALAT-1 is expressed in a variety of tissues but is enriched in the brain where it controls the expression of a subset of genes sig- nificantly associated with synaptogenesis. One of the hallmarks of human brain evolution is the expanding complexity of synap- tic networks and the controlled expression of specific lncRNAs in neuronal cells.27,28 Transcriptomics studies have revealed the dynamic expression profile of several lncRNAs during the mat- uration of neuronal cell subtypes.29 Some studies revealed the presence of “brain-associated” lncRNAs that affect hippocam- pal development, oligodendrocyte myelination and aging in the brain.30 Thus, it is not surprising that the alteration of lncRNAs 860 rNA Biology volume 9 issue 6