Mulder and Scully. Holmes and Watson. If TV and books are anything to go by, then unconventional pairings between the hot-headed detective and their calm and collected partner get results. Now it seems that another unlikely duo work together in the fight against crime of a biological nature. A new study reports that a DNA methyltransferase teams up with a long non-coding RNA to suppress the growth of colon tumors.
Our genome encodes thousands of long non-coding RNAs (lncRNAs). For years these molecules were overlooked, but now they are implicated in many aspects of mammalian biology, and are dysregulated in various diseases, including cancer. This is not surprising given their ability to act as a scaffold for epigenetic enzymes, co-activators, or repressors for transcription factors, and ‘sponges’ for microRNAs.
To determine whether lncRNAs also control genomic output by regulating DNA methylation, lead author Ahmad Khalil and his team immunoprecipitated the DNA methyltransferase DNMT1 from human colon cancer cells and sequenced bound RNA by next-generation RNA sequencing.
With some biological detective work, here’s what they found:
- DNMT1 likes to partner up with lncRNAs, and may cooperate with more than 100 of them.
- One lncRNA in particular earned the title ‘DNMT1-associated Colon Cancer Repressed lncRNA-1’ (DACOR1) because it was strongly expressed in normal colon tissues but repressed in colon tumors and cell lines.
- DACOR1 localizes to genomic sites known to be differentially methylated in colon cancer tumors.
- Colon cancer cells forced to express DACOR1 showed differential methylation at least 50 CpG sites, as well as impaired growth and colony formation.
- The induction of DACOR1 affected the expression of 99 genes, including the downregulation of cystathionine β-synthase (CBS), which can increase levels of methionine, the substrate needed to generate S-adenosyl methionine (SAM).
Thus, the DNMT1 and DACOR1 duo appear to police the genome of colon cancer cells by indirectly regulating levels of SAM and hence global methylation. Lead author Khalil says that “these findings are highly significant because they provide a potential mechanism of how cancer cells alter their epigenome without mutating DNA methyltransferases”.
To see this cancer-fighting duo in action, check out Human Molecular Genetics, August 2015.