The rise of regulatory RNA

Abstract

Discoveries over the past decade portend a paradigm shift in molecular biology. Evidence suggests that RNA is not only functional as a messenger between DNA and protein but also involved in the regulation of genome organization and gene expression, which is increasingly elaborate in complex organisms. Regulatory RNA seems to operate at many levels; in particular, it plays an important part in the epigenetic processes that control differentiation and development. These discoveries suggest a central role for RNA in human evolution and ontogeny. Here, we review the emergence of the previously unsuspected world of regulatory RNA from a historical perspective.

Figure 1. Complex expression of the genome and examples of non-coding RNA expression

Graphical representation of the mammalian transcriptional landscape with genes expressing rRNAs, tRNAs, snRNAs, snoRNAs, various protein coding and non-coding transcripts (mRNAs and lncRNAs), as well as small regulatory RNAs including miRNAs, piRNAs, tiRNAs and spliRNAs, snoRNA-derived small RNAs, and tRNA-derived small RNAs.

Figure 2. Functional pathways of small regulatory RNAs

(A) miRNA precursors are expressed as stem-loop structures, which (B) interact with Drosha and DGR8, where they are processed then exported from the nucleus by Exportin 5. (C) These transcripts are further processed by Dicer to small (21–23 nt) dsRNAs, one strand of which is loaded into AGO component of the RNA-induced silencing complex (RISC). Exogenously introduced siRNAs can also be processed by RISC. Either the endogenous miRNA or exogenously added siRNAs can then to target (D) the repression of translation and/or (E) cleavage of homology containing transcripts^,. Some small RNAs are functional in the nucleus. (F) Exogenously introduced small antisense RNAs (asRNAs) can target epigenetic silencing of targeted loci^,,, a pathway that miRNAs may also utilize in the nucleus. (G) tiRNAs and spliRNAs^, are also expressed through an unknown pathway that may involve RNAPII backtracking and TFIIS cleavage, with the tiRNAs shown to modulate CTCF chromatin localization and to be associated with nucleosome position.

Figure 3. Various roles for lncRNAs in cellular regulation

(A) Long non-coding RNAs are expressed from many loci in the genome, sense and antisense, intronic, overlapping and intergenic with respect to nearby protein-coding loci, and function both in cis and trans. (B–E) Some lncRNAs interact with proteins to control the access of chromatin to cellular components and/or guide epigenetic regulatory complexes to target loci resulting in both (B) transcriptional suppression and (C) activation or suppression (bimodal control). Proteins involved in chromatin modification such as DNMT3a, EZH2 and PRC2 complexes have been associated with epigenetic targeted lncRNA regulation^,,. (D) Some lncRNAs function to tether distal enhancer elements with their promoters^,. (E) LncRNAs can also function by binding proteins to sequester them away from their sites of action (decoy lncRNAs) while other lncRNAs can interact with each other and/or function to sequester small regulatory RNAs such as miRNAs and therefore RISC targeting complexes away from protein-coding mRNAs^,,. (G) LncRNAs can also act as translational inhibitors by binding and sequestering mRNAs away from the translational machinery while other lncRNAs (H) appear to regulate splicing.