About 90% of our genome is transcribed, but only 1-2% of the transcripts encode proteins. So what are all of those non-coding RNAs (ncRNAs) doing? A better question might be: what aren’t they doing? In addition to regulating gene expression at the transcriptional and post-transcriptional levels, ncRNAs play a big part in the control of epigenetic pathways.
More functional categories of ncRNAs have recently been identified, and you can be sure that more are on the way. Trying to keep microRNAs (miRNAs), Piwi-interacting RNAs (piRNAs), small interfering RNAs (siRNAs), long non-coding RNAs (lncRNAs) , not to mention the subgroup, large intergenic non-coding RNAs (lincRNAs), the newly described enhancer RNAs (eRNAs) and promoter-associated RNAs (PARs) all straight can be quite daunting.
We sometimes get asked why we cover ncRNAs along with other, more established epigenetic mechanisms. Thankfully Christopher Glass and his team at UC San Diego have taken it upon themselves to review all of the known types of ncRNAs and their epigenetic relationships to help make the case that ncRNAs belong in the same category as DNA Methylation and Chromatin. Some examples of their varied roles include:
- RNA Directed Gene Silencing: Since components of both Polycomb group (PcG) complexes PRC1 and PRC2 bind RNA, ncRNA-directed silencing can involve the recruitment of the PcG complexes.
- Chromatin Modification: lincRNAs bring chromatin-modifying complexes to specific loci. For instance, Xist recruits PRC2 to the inactive X chromosome while ANRIL recruits PRC1 and PRC2 to the INK4 tumor suppressor gene. HOTAIR (HOX antisense intergenic RNA) brings both PRC2 and LSD1 to silence the HOXD cluster.
- Structural Changes to Chromatin: eRNAs are produced from enhancers enriched in H3K4me1 and may contribute to a more open chromatin structure and help bring enhancers and promoters together through chromatin looping.
- Gene Promoter Regulation: PARs from PcG target genes are bound by PcG complexes and are not produced from active promoters. This suggests that PARs help keep PcG complexes tethered to silenced promoters and allow them to be easily released upon gene activation.
The focus on epigenetic alterations in human diseases has rapidly expanded from cancer to include, among many others, cardiac disease. This review makes it clear that the study of epigenetics must expand from just DNA methylation and histone modifications to include ncRNAs since they help to maintain a poised chromatin state and mediate epigenetic modifications.
Need help keeping all of the ncRNAs straight in your head? Get a cheat sheet to pin up at your desk, and the complete review at Cardiovascular Research May 2011.