Finding the links between DNA methylation and histone modification is no easy chore. Long non-coding RNAs (lncRNAs) may be the answer; they are a huge part of the transcriptome, and many appear to be functional. There is growing evidence that lncRNAs act to “lnc” other epigenetic regulators together and coordinate their function. Adding to that evidence is the lncRNA PARTICLE (Gene PARTICL- ‘Promoter of MAT2A-Antisense RadiaTion Induced Circulating LncRNA), which accelerates our understanding of epigenetic coordination.
PARTICLE controls a negative feedback loop where the expression of a neighbouring gene (MAT2A) is reduced following PARTICLE’s upregulation after radiation exposure in humans. In order to accomplish this, PARTICLE binds the DNA at the MAT2A promoter, which increases DNA methylation and results in transcriptional silencing. It also binds the Polycomb Repressive Complex 2 (PRC2) subunit, Suppressor of Zeste 12 (SUZ12), which regulates the repressive H3K27me3 activity of the complex. In order to untangle this complex web of links, the lab of Michael John Atkinson at the German Research Center for Environmental Health sorted out the functional consequences of these interactions. Here’s what they found in their cell lines:
- PARTICLE upregulation alters both local and global H3K27me3, as determined by ELISA and ChIP-seq
- By using a broccoli tag sequence cloned to PARTICLE, the lncRNA was visualized interacting with DNA methyltransferase 1 (DNMT1) using flow cytometry, mobility shift gels, and co- immunoprecipitation assays
- DNMT1 function was boosted when PARTICLE was over-expressed
- Global and gene-specific DNA methylation levels are increased by PARTICLE
From this study, it appears that PARTICLE has a much broader influence over the epigenome than previously thought. It affects both DNA methylation and H3K27me3 and physically links their writers. From these data, the authors propose that PARTICLE acts as a regulatory docking platform, bringing together DNA methylation and histone methylation machinery to direct the transcriptional response to an environmental challenge. Though many previously characterised lncRNAs are involved in either DNA methylation or histone modification, this is an example of one that interweaves the two.
Check out all the links over at Scientific Reports, May 2017