The holidays are just around the corner, but the gifts are arriving early as a talented crew of epigenetics enthusiasts published some great work in Nature last week that suggests some RNA transcripts have more self control than a Jedi. Look out Luke, these under appreciated RNAs fit DNMT1 like a glove, and block local DNA methylation.
Dr. Daniel Tenen and his colleagues at Harvard Medical School had suspicions that active transcription might regulate levels of genomic DNA methylation, and dove in to the methylation dynamics of the well-known methylation-sensitive gene CEBPA, including the potential involvement of non-coding RNAs (ncRNAs) originating from that locus. Here’s what they uncovered:
- Active transcription can regulate levels of genomic methylation.
- The novel RNA ecCEBPA, arising from the CEBPA gene locus, is critical in regulating the local DNA methylation profile.
- ecCEBPA binds to DNMT1 and prevents CEBPA gene locus methylation.
- Deep sequencing of DNMT1-interacting RNAs (DiRs), along with genome-scale methylation and expression profiling revealed that the same type of regulation occurs at numerous gene loci.
The researchers say that, “Collectively, these results delineate the nature of DNMT1–RNA interactions and suggest strategies for gene-selective demethylation of therapeutic targets in human diseases.”
DNMT1-interacting RNAs (DiRs): A Target and Tool of the Future?
Dr. Tenen shared with us that there are still some questions left to be answered. “The DiRs are poly A-, maybe [even] nuclear, RNA’s that no one is looking at. What else does it do? What other RNA ‘worlds’ are there in the cell not currently studied?” Tenen already has plans for future experiments, “We can use RNA to induce gene selective methylation. What is not in the paper is that we can design CRISPR-like RNA guide oligos connected to RNA promoter sequences, which can induce demethylation of CEBPA…We are now testing this method with other gene loci.”
Tenen admits his surprise “that no one had ever asked whether DNMT1 bound RNA with high affinity and function, since it seems likely that anything that binds DNA will also bind RNA, and others have previously shown DNMT2 binds to RNA.” “There are unexplored RNA worlds in the ‘cellular solar system’, and some of them regulate epigenetic marks such as DNA methylation.”
Get a glimpse at this new RNA world at Nature, October 2013