Non-coding RNAs: key regulators of mammalian transcription

Abstract

Non-coding RNAs (ncRNAs) are now recognized as active participants in controlling many biological processes. Indeed, these products of transcription can even control the process of transcription itself. In the past several years, ncRNAs have been found to regulate transcription of single genes, as well as entire transcriptional programs, affecting the expression of hundreds to thousands of genes in response to developmental or environmental signals. Compared to more classical protein regulators, the list of ncRNAs that regulate mRNA transcription in mammalian cells is still small; however, the rate at which new ncRNA transcriptional regulators are being discovered is rapid, suggesting that models for how gene expression is controlled will continue to be redefined as this field develops.

Figure 1

ncRNAs that regulate chromatin structure. (a) HOTAIR represses transcription by recruiting chromatin modifying complexes to specific regions of the genome. HOTAIR acts as a scaffold that can simultaneously bind PRC2 and LSD1, which methylate H3K27 and demethylate H3K4, respectively. (b) ANRIL represses transcription from the INK4b/ARF/INK4a locus by recruiting PRC1 and PRC2. The mechanism might involve an ANRIL transcript tethered to a Pol II elongation complex serving to recruit PRC1 and PRC2 [19]. (c) HOTTIP mediates long-range looping at one end of the HOXA locus, and activates transcription of genes by recruiting the histone modifier WDR5-MLL, which methylates H3K4.

Figure 2

ncRNAs that regulate transcription factors. (a) Gas5 ncRNA serves as a mimic of the DNA site to which GR binds. By keeping GR from binding GREs, Gas5 blocks the activation of GR-responsive genes. (b) B2 RNA binds directly to Pol II during the heat shock response. It represses transcription by building into complexes with Pol II at promoters and keeping the polymerase from engaging the DNA as well as blocking phosphorylation of the Pol II CTD by TFIIH. The schematic was adapted with permission from [34]. (c) 7SK RNA, which is found in a complex minimally with P-TEFb, LARP7, and HEXIM1 or HEXIM2, represses the P-TEFb kinase, which is responsible for phosphorylating Ser2 residues in the Pol II CTD during early elongation. (d) lincRNA-p21 recruits hnRNP-K to many p53-responsive genes and mediates repression of these genes. (e) SRA binds many proteins and macromolecular complexes (some of which are shown) to mediate transcriptional regulation. Moreover, through its association with the RNA helicase p68 and CTCF, SRA plays a crucial role in insulating genes from one another throughout the genome.