A novel role for Alu elements in epigenetic trans-regulation of gene networks

Screen Shot 2013-07-26 at 9.42.44 PMEver so often, you stumble across a magnificent work of science. This was the case for me a few weeks ago when this work popped up in my news feed. The authors investigate how a genomic locus that is the strongest risk factor for artherosclerosis produces a regulatory non-coding gene that regulates other genes associated to the disease.

They used stable over-expression and knock-down approaches to investigate the role of distinct ANRIL (a long non-coding RNA, aka lncRNA) isoforms in several key mechanisms of atherogenesis. They show that this gene guides epigenetic effector complexes to specific genomic loci.

Through what molecular mechanism you ask? None other than via endogenous transposable elements–ALUs specifically–that have been harnessed through evolution to perform regulation of gene expression in our genomes. FYI, repetitive elements compose ~46% of the human genome, 20% of which are ALUs.

The study shows that these genomic repeats, often considered to be bona fide “junk” DNA, form a regulatory network of motifs that specifically guide the regulation of arteriosclerosis gene expression. These repetitive DNA elements are present both in the ANRIL lncRNA and in the promoters of the target genes, and that these elements are required for specific recruitment of the epigenetic machinery. This suggests that evolution has adopted (or domesticated) viral DNA sequences in our genome as a molecular template to forge regulatory networks. 

Using RNAi against ANRIL, the authors demonstrate impaired recruitment of chromobox homolog 7 (CBX7), a member of Polycomb repressive complex 1 (PRC1), and of suppressor of zeste 12 (SUZ12), a member of PRC2, to the Chr9p21 region. This region is the strongest genetic risk factor for arteriosclerosis. Knocking down ANRIL decreased trimethylation of lysine 27 residues in histone 3 (H3K27me3), an epigenetic mark of reduced gene expression activity (inhibition of transcription).

Furthermore, regulatory motifs were characteristic for ANRIL-regulated genes. The functional relevance of the motifs were confirmed by deletion and mutagenesis and results were validated in primary human cells from patients with and without the Chr9p21 atherosclerosis risk allele.

Overall, this work is an exquisite example of detailed mechanistic functions of lncRNAs, as well as a seminal example of how repetitive elements have been domesticated into regulatory networks. This raises the question of how do RNA-DNA elements interact at the biochemical level to provide target specificity? Could pyknons serve as a template for a more widespread RNA-DNA regulatory network?

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