*2.1. Biogenesis, Structure, and Function of Linear lncRNAs*

The biogenesis of lncRNAs is like mRNA biogenesis since this process is mediated by RNA polymerase II. Similar to mRNA molecules, lncRNAs are characterized by alternative splicing, a 50 7-methylguanosine cap, and a 30 poly (A) tail, although there is evidence that certain lncRNAs lack the 50 -cap or 30poly (A) tail [30]. A comparison of the global features of lncRNAs and mRNAs shows that lncRNAs are less abundantly expressed, have less stability, are less evolutionarily conserved, and contain fewer numbers but longer exons [31]. The expression of lncRNAs is considered more cell- or tissue-specific than mRNA expression [32].

lncRNAs can be transcribed from the intergenic, exonic, or distal protein-coding regions of the genome. Based on genomic locations and orientation, lncRNAs can be classified into intergenic, intronic, sense, and antisense lncRNAs [33]. Intergenic lncRNAs (long intergenic noncoding RNAs or lincRNAs) are located between two protein-coding genes and transcribed in the same direction as those genes. Intronic lncRNAs are located entirely within the intronic region of a protein-coding gene and do not overlap with any exon. Sense lncRNAs are transcribed from the same strand and in the same direction as the protein-coding gene, possibly being exonic and/or intronic. Antisense lncRNAs are transcribed from the opposite strand of the protein-coding gene and can also be exonic and/or intronic. Pseudogene-derived RNAs are key components of lncRNAs with important functions in multiple biological processes [34].

Functionally, lncRNAs are classified under the mechanisms of action into these categories: signals (gene activators), decoys or sponges (gene repressors), guides (gene expression regulators), scaffolds (chromatin modifiers), and enhancer RNAs (eRNAs) [31,35]. As signals, lncRNAs function alone or combined with transcription factors or signaling pathways to activate transcriptional activity in time and space. As decoys, lncRNAs bind to functional sites to titrate the transcription factors away from chromatin or titrate miRNAs away from their targets to modulate transcription. As guides, lncRNAs recruit regulatory proteins to form ribonucleoprotein (RNP) complexes and direct them to their target sites to regulate the expression of target genes, either in cis or in trans. As scaffolds, lncRNAs provide platforms to bring different proteins together to form RNP complexes to activate or repress transcription. eRNAs are regulatory sequences from enhancer regions that in cis regulate the expression of target genes. LncRNAs can be nuclear, cytoplasmic, or both, and the subcellular localization determines its function [31,35].
