The role of long non-coding RNAs in genome formatting and expression

Abstract

Long non-coding RNAs (lncRNAs) are transcripts without protein-coding potential but having a pivotal role in numerous biological functions. Long non-coding RNAs act as regulators at different levels of gene expression including chromatin organization, transcriptional regulation, and post-transcriptional control. Misregulation of lncRNAs expression has been found to be associated to cancer and other human disorders. Here, we review the different types of lncRNAs, their mechanisms of action on genome formatting and expression and emphasized on the multifaceted action of the H19 lncRNA.

Keywords: H19; chromatin organization; lncRNAs; post-transcriptional control; transcriptional regulation.

FIGURE 1

Functional mechanisms of long non-coding (lncRNA) action at the post-transcriptional levels. (A) mRNA stabilization. Base pairing between specific regions of a long non-coding antisense RNA and its sense transcript induces stabilization of the target mRNA and increases protein abundance. (B) mRNA degradation. Staufen double-stranded RNA-binding protein 1 (STAU1)-mediated mRNA decay is induced when base pairing is formed between the mRNA and a lncRNA. (C) Ribosome targeting. Through homologous base pairing with mRNAs and interactions with ribosomal proteins lncRNAs target transcripts to ribosomes or prevent translation. (D) Regulation of splicing. Base pairing between mRNAs and lncRNAs may prevent splicing by masking the splicing sites. In addition, lncRNAs are also implicated in the formation and maintenance of nuclear structures involved in alternative splicing of nascent transcripts. (E) miR sponge. By sequestering miRs through base pairing formations, lncRNAs affect the expression of the miR target genes. (F) Precursor of miRs. LncRNAs can serve as a source of miRs after processing. LncRNAs are shown in red, whereas mRNAs are in blue. See text for examples.

FIGURE 2

Functional mechanism of action at the levels of transcriptional regulation. (A) LncRNA may regulate transcription by virtue of RNA–DNA triplex formation preventing the formation of the transcription initiation complex at promoters. (B) LncRNAs can act as decoys by titrating transcription factors away from their cognate promoters. (C) LncRNAs can regulate transcription through the targeting of transcription factors to promoters or acting as co-factors involved in transcription factor activity. (D) LncRNA can also control transcription factor trafficking. LncRNAs are shown in red.

FIGURE 3

Examples of lncRNAs controlling chromatin organization. (A) HOTAIR (HOX transcript antisense RNA) represses transcription in trans by recruiting two different chromatin modifying activities. The Polycomb Repressive Complex 2 (PRC2) produces the repressive H3K27me3 marks, whereas the LSD1-CoREST complex is responsible for the removal of the active H3K4me2/3 marks. (B) The ANRIL lncRNA represses transcription in cis at the INK4B/ARF/INK4A locus by recruiting the Polycomb repressive complexes PRC1 and PRC2. (C) The HOTTIP (HOXA transcript at the distal tip) lncRNA activates genes by recruiting the histone modifier complex WDR5-MLL which is responsible for H3K4me3 methylation, and by mediating long-range chromatin looping at one extremity of the HOXA locus. Purple hexagons represent H3K27me3 repressive marks, whereas green hexagons illustrate H3K4me3 activating marks.

FIGURE 4

Schematic representation of the transcriptional complexity at the H19/IGF2 locus. Non-coding transcripts at the H19/IGF2 are shown as blue squares when they are expressed. Coding genes are in green, when expressed. The differences in gene expression between the paternal and maternal alleles are shown. The DNA methylation status of the regulatory elements ICR (imprinting control region) and DMRs (differentially methylated regions) is indicated for the paternal and maternal alleles.

FIGURE 5

The multifaceted action of the lncRNA H19. The lncRNA H19 controls genome expression at multiple levels. H19 acts on chromatin organization through the recruitment of chromatin modifying complex PRC2 (1) and on post-transcriptional control as a miR decoys sequestering miR-106a and miR-let7 (2) or as a precursor for miR-675-5p and miR-675-3p (3) H19 also interact with p53 (TP53) and inactivate the tumor suppressor protein action (4) Furthermore, possible base pairing between H19 and the antisense transcripts 91H and HOTS may have biological outcomes (5).