Regulation of gene expression by long non-coding RNAs

Gene regulation is a really complicated thing. We have covalent marks to DNA, histones and transcription factors. Chromatin remodeling and long range enhancer interactions. Enhancer elements located in introns of genes hundreds of kilobases away from the gene they're controlling. Transcriptional control from microRNA networks and now there is an emerging model for the function of some of the thousands of long non-coding RNAs which are just now being uncovered with high resolution (directional) transcriptome analysis.

Many of you which studied molecular biology at Uni would (should) remember the model for how X chromosome inactivation is achieved. The mechanism centers around XIST, one of the first non-coding RNA genes identified. Expression of XIST from the inactive X chromosome essentially wraps it up at the same time that repressive epigenetic marks are established through its interaction with the Polycomb Repressive Complex 2 (PRC2). Sounds simple enough, but the model also involves two other non-coding RNA genes JPX and FTX as well as two protein coding genes TSX and CNBP2.

But there's one problem, how does XIST keep expression up when the rest of the chromosome is becoming repressed? Well the answer lies in the action of TSIX the antisense transcript of XIST. 
High levels of the TSIX transcript from the locus compete for the binding of PRC, so when TSIX expression is low, PRC2 is free to start binding with the XIST RNA RepA. This RepA/PRC2 complex then loads onto XIST chromatin with the help of YY1 and confers DNA methylation, at which point XIST RNA is transcribed, leading to methylation of the entire chromosome guided by PRC2.

More generally, the emerging model of lncRNA action involves the transcription of the lncRNA followed by pausing of the POL2 transcription complex resulting in an RNA tail attached at the 3' end but freely swimming around at the 5' end. The ncRNA contains a tethering or binding motif which can be targeted by proteins such as PRC2. The PRC2 complex can then be pulled to the chromatin by factors which bind RNA and DNA simultaneously such as YY1. This mechanism enables large complexes such as PRC2 to be recruited to the chromatin to deposit epigenetic marks on nearby genes.

Traditionally transcriptional control is thought to be mediated by transcription factors binding to DNA motifs in promoters where epigenetic modifications are permissive, but this new model highlights that transcription factors and chromatin remodellers might actually be dependent on lncRNAs for additional locus specificity. Moreover, this model provides a mechanism for the understanding of the long-range (hundreds of kilobases even interchromosomal) chromatin interactions that are apparent in ChIA-PET, 5C and DNase hypersensitivity profiling datasets.

The lessons learned from Xist in the field of epigenetics over the past 20 or so years are becoming mainstream ideas in modern molecular biology. It also seems that an understanding of the importance of DNA methylation cannot be complete without understanding the RNA neighborhood.


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