If you live near a construction site, are listening to one half of a cell-phone conversation in a movie theater, or stuck on an airliner next to a fussy infant, then for you silence may indeed be golden. But, for certain ultraconserved non-coding RNAs, transcriptional silencing can lead to a cellular uproar.
A new article in Oncogene details how silencing of transcribed ultraconserved regions (T-UCRs) by CpG island hypermthylation is associated with cancerous consequences. The work, churned out from the labs of epigenetic heavyweights Carlo Croce, George Calin and Manel Esteller, focused on T-UCRs, a class of non-coding RNAs that are perfectly conserved across analogous regions in human, mouse and rat genomes, which were being repressed by hypermethylation. The group used custom-designed UCR arrays, and the DNA demethylating drug 5-aza-2’-deoxycytidine (AZA) to uncover three T-UCRs (Uc.160+, Uc.283+A and Uc.346+) that had low expression in colon cancer cells (HCT-116), were upregulated after AZA treatment, had a CpG Island within 2Kb of the UCR, and showed cancer specific methylation.
The researchers zeroed in to get a more in-depth look at Uc.160+, Uc.283+A and Uc.346+. They saw that the UCRs in HCT-116 colon cancer cells, with hypermethylated UCR CpG islands, showed:
- Fewer H3K4me3 mods, associated with active transcription, than AZA treated cells in ChIP experiments
- Lower chromatin accessibility measured by MspI assays
- Less RNA polII present at T-UCR CpG Islands in pulldown assays.
The same T-UCR CpG island hypermethylation profile was also found in many other cancer cell lines including colon, breast, lung, lymphoma and leukemia samples. All of the data they generated helped to determine relationships between CpG island hypermethylation, ncRNA transcriptional silencing, chromatin structure and tumorigenesis. The authors suggest that further study of T-UCRs could lead to the development of potential cancer biomarkers or a new therapeutic uses for demethylating agents.
You do not have the right to remain silent about this paper! Check it out at Oncogene, August 2010.