ncRNA mediated modes of gene regulation (TGS and TGA)
Figure 1 (of 6)
Model for non-coding RNA directed transcriptional gene silencing (TGS) in human cells. (A-C) Small antisense non-coding RNAs can be generated (sequences determined via the use of a computational algorithm) to target silent state epigenetic changes to targeted loci. The result of this targeting is the epigenetic remodeling of the target locus, which results in transcriptional gene silencing of the target site. (D-E & C) Recent findings suggest that long non-coding RNAs, that are antisense to gene promoters and possibly expressed from bidirectionally transcribed loci, are endogenous effectors driving this process in human cells (reviewed in (Knowling and Morris, 2011; Morris, 2009)).
Figure 2 (of 6)
Model for transcriptional gene activation (TGA) or de-repression of gene expression in human cells. Genes that are under long non-coding RNA mediated transcriptional regulation (A-D) can be targeted with small RNAs or antisense oligonucleotides (E-F) leading to a loss of RNA directed transcriptional gene silencing and subsequence gene activation/de-repression. Examples of gene activation can be found with tumor suppressor genes PTEN, p21, p15 and with the transcription factor Oct-4 (Hawkins and Morris, 2010; Johnsson et al., 2013; Morris et al., 2008; Yu et al., 2008).
Figure 3 (of 6)
Pseudogene mediated regulation of PTEN transcription and translation. (A) The PTEN pseudogene 1 (PTENpg1) expresses both sense and 2 antisense isoforms from chromosome 9 in human cells. (B) The alpha PTENpg1 antisense variant functions in Trans to target epigenetic silencing complexes consisting of DNMT3a and other possible proteins such as EZH2 to the promoter for the PTEN protein-coding gene on chromosome 10 resulting in (C) epigenetic and transcriptional silencing. (D) The beta PTENpg1 antisense variant interacts in an RNA:RNA dependent manner to (E) localize PTENp1 sense transcripts to the cytoplasm where miRNA sponging may occur. This model is based on work presented in Johnsson et al (Johnsson et al., 2013).
Figure 4 (of 6)
Model for HIV-encoded antisense lncRNA mediated regulation of viral transcription. (A) A long non-coding RNA (lncRNA) antisense to the viral genome is transcribed from a putative promoter within the nef gene (Kobayashi-Ishihara et al., 2012; Landry et al., 2007). (B) This HIV expressed lncRNA recruits DNMT3a and possibly other chromatin remodeling proteins (Enhancer of Zeste 2 (EZH2), Histone deacetylase 1 (HDAC-1), G9a) and (C) guides these proteins to the viral promoter. (D) The localization of the chromatin remodeling complex at the viral promoter results in the formation of heterochromatin based silencing, a chromatin state at the viral promoter that ultimately results in transcriptional shutdown and epigenetic silencing. (E) The HIV-encoded lncRNA can be inhibited by the action of small single stranded RNAs targeted to the promoter driving expression of the HIV expressed antisense lncRNA via transcriptional gene silencing (refer to figure 1), or by small RNAs or antisense oligonucleotides targeted to the HIV antisense lncRNA via post-transcriptional gene silencing (shown). (F) Ultimately, the inhibition of the antisense lncRNA prevents the recruitment of chromatin remodeling proteins to the viral promoter and (G) transcriptional derepression.This figure was adapted from (Saayman et al., 2014).
Figure 5 (of 6)
Model for MYCNOS mediated cis regulation of MYCN/MYCNOS locus. (A) MYCN is expressed as 2 isoforms from either promoter 1 or promoter 2. Promoter 2 is bidirectional promoter which is downstream of promoter 1 and also the promoter driving MYCNOS expression. (B) increased MYCNOS expression leads to epigenetic silencing of promoter 1 and also promoter 2 (promoter 1 is shown here). (C) The resulting silencing results in increased MYCN (exon2/3 expression from promoter 2. This model is adapted and based on studies carried out in (Vadie et al., 2015).
Figure 6 (of 6)
Model for BGas (EST BG213071) regulation of CFTR expression- (A) The CFTR locus is shown with the internal expressed BG213071 and truncated CFTR transcript NM_000492. (B) The BG213071 lncRNA is expressed and localizes to the homology containing locus in the CFTR gene body. The localization of BG213071 to it’s target locus allows for chromatin structural and DNA binding proteins such as HMG-14, HMG-17, HMGB1 and WIBG to localize specifically to the CFTR gene body and affect the local structure of the gene ultimately diminishing RNAPII activity.