Abstract
Long non-coding (lnc) RNAs are defined as non-protein coding RNAs distinct from housekeeping RNAs such as tRNAs, rRNAs, and snRNAs, and independent from small RNAs with specific molecular processing machinery such as micro- or piwi-RNAs. Recent studies of lncRNAs across different species have revealed a diverse population of RNA molecules of differing size and function. RNA sequencing studies suggest transcription throughout the genome, so there is a need to understand how sequence relates to functional and structural relationships amongst RNA molecules. Our synthesis of recent studies suggests that neither size, presence of a poly-A tail, splicing, direction of transcription, nor strand specificity are of importance to lncRNA function. Rather, relative genomic position in relation to a target is fundamentally important. In this review, we describe issues of key importance in functional assessment of lncRNA and how this might apply to lncRNAs important in neurodevelopment.
Highlights
THERE IS A WIDE VARIETY OF NON-CODING RNA IN MANY SPECIES The co-occurrence of massively parallel sequencing technology applied to RNA and the recognition that non-coding, functional RNA species may not be restricted to X-chromosome inactivation (Jeon et al, 2012; Batista and Chang, 2013) or to protein synthesis machinery, have revealed an RNA universe of remarkable diversity in plant and animal cells
Subsequent identification of ncRNAs unrelated to protein synthesis over 25 years ago, the catalytic ribozymes that formed secondary and tertiary structures thought to be important to early life on earth, re-enforced the diversity of RNA species (Sharp, 1985; Lamond and Gibson, 1990)
CHARACTERIZATION OF lncRNAs Several recent reviews have delineated ncRNA species into subcategories based on size, position (e.g., RNA species generated from the 3 UTRs or 5 UTRs), molecular interactions (e.g., Drosha- or Dicer-dependent), and molecular function, a good example of which is competitive antisense (AS) RNA that binds to microRNA and acts as a sponge to inhibit competitively microRNA from binding to a sense mRNA transcript (Cesana et al, 2011)
Summary
CHARACTERIZATION OF lncRNAs Several recent reviews have delineated ncRNA species into subcategories based on size (less or greater than 200 bases – often used as the definition of long versus short ncRNA), position (e.g., RNA species generated from the 3 UTRs or 5 UTRs), molecular interactions (e.g., Drosha- or Dicer-dependent), and molecular function, a good example of which is competitive antisense (AS) RNA that binds to microRNA and acts as a sponge to inhibit competitively microRNA from binding to a sense mRNA transcript (Cesana et al, 2011) It is unclear whether these categories are empirically determined, or whether they will prove relevant to categorization as future ncRNAs are discovered; the identification of such a wide diversity of RNA is consistent with what might be expected from an ancient, flexible molecule, capable of forming 3D structures and interacting with DNA, protein, or other RNAs. What makes a lncRNA a lncRNA rather than some other RNA species? The lncRNA IRT1 differs significantly from the mechanistic action of COLDAIR, and functions in a repressive manner to block expression of the target gene IME1. The blocking of transcription factors in combination with aiding in the establishment of a repressive chromatin state through histone methyltransferases
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