ReviewRoles of long noncoding RNAs in brain development, functional diversification and neurodegenerative diseases
Introduction
Over the last decade, advances in genome-wide analysis of the eukaryotic transcriptome have revealed that up to 90% of the human genome are transcribed, however, GENCODE-annotated exons of protein-coding genes only cover 2.94% the genome, while the remaining are transcribed as noncoding RNAs (ncRNAs) (ENC Project and Consortium, 2012). Noncoding transcripts are further divided into housekeeping ncRNAs and regulatory ncRNAs. Housekeeping ncRNAs, which are usually considered constitutive, include ribosomal, transfer, small nuclear and small nucleolar RNAs. Regulatory ncRNAs are generally divided into two classes based on nucleotide length. Those less than 200 nucleotides are usually referred to as short/small ncRNAs, including microRNAs (miRNAs), small interfering RNAs and Piwi-associated RNAs, and those greater than 200 bases are known as long noncoding RNAs (lncRNAs) (Nagano and Fraser, 2011).
The crucial role of miRNAs in post-transcriptional gene regulation by repressing gene expression via targeting semi-complementary motifs in target mRNAs has been highlighted (Lee et al., 1993). An abundance of studies showed the disrupted miRNAs in cancer (Liu et al., 2012), stroke (Wu et al., 2012), neurological diseases (Bian and Sun, 2011), suggesting the miRNAs must play some roles in disease pathologic process, diagnosis, prognosis, and also with the potential as promising treatment targets. lncRNAs have been attracting intense interest with the attractive possibility to find new molecules and mechanisms that could shed light on the explanation of organismal complexity and complex diseases.
The central nervous system (CNS) is the most highly evolved and sophisticated biological system. It is comprised of an enormous array of neuron and glial cell subtypes which distributed at the strict and precise region, forming into dynamic neural networks responding with internal signal and external stimulation, then responsible for mediating the complex functional repertoire of the CNS including performing higher order cognitive and behavioral (Graff and Mansuy, 2008). NcRNAs and their associated orchestrated networks are highly adapted to the complex repertoire of neurobiological functions. lncRNAs, as one of the most abundant classes of ncRNAs, which transcribed from the different location of genome are highly expressed in brain (Ravasi et al., 2006, Mercer et al., 2008, Ponjavic et al., 2009). The roles of lncRNAs in brain development, neuron function, maintenance, differentiation and neurodegenerative diseases are becoming increasingly evident. For the purpose of this review, we will firstly give a systematic and comprehensive profile of lncRNAs based on the existing knowledge, and highlight their expression and function involved in CNS development, functional maintenance and neurodegenerative disease.
Section snippets
Definition of lncRNAs
The initial lncRNAs, such as XIST (X-inactive specific transcript) and H19 were first discovered by searching cDNA libraries for clones in 1980s and 1990s (Brown et al., 1991, Bartolomei et al., 1991). With the improvement of microarray sensitivity and sequencing technology, an abundance of lncRNAs transcripts have been found (Kapranov et al., 2007). However, unlike miRNAs, as lacking of uniform systematic annotation systems cause the same lncRNAs with different names in science literatures,
lncRNAs in the central nervous system
The primate nervous system is most elaborate in biological system. Understanding their molecular mechanisms is a big challenge and a subject interest among a lot of scientists. Noncoding sequences associated with human neural genes exhibit prominent signatures of positive selection and accelerated evolution, which provide new avenues to link genetic and phenotypic changes in the evolution of the human brain. The flexible and complex functions of lncRNAs coincides with the diversity and
Perspective and challenge
The landscape of current knowledge on lncRNAs has considerably changed over the last few years, and will likely continue to change substantially in the coming years. It is obviously clear that lncRNAs have numerous molecular functions, including epigenetic modification, translation and post-translation. Their complexity supports the proposition that evolutionary innovations and expansion of regulatory RNAs are fundamental reasons for the organic complexity of eukaryotes.
There are still some
Acknowledgements
Authors acknowledge the support given by the Joint Project of the Chinese Academy of Sciences and the Guangdong Province Guangdong Science and Technology Plan Project (Project No. 2009B091300129); and the Science and Technology Development project of Guangzhou (Project No. 2010UI-E00531-7).
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The authors contributed equally to this work and should each be considered co-first author.