Even with all the advanced communications at our fingertips today, long distance relationships rarely work out, but it appears epigenetic silencing is an exception. Epigenetic silencing can spread to neighboring genomic regions through long-range epigenetic silencing (LRES) in cancer cells. In LRES, large blocks of genomic regions (like on the order of megabases) get silenced. Recently, researchers in Australia and Atlanta teamed up to do some sleuthing about this LRES phenomenon that we also mentioned in an article about the 3rd International Epigenetics Conference. They found a bevy of repressive epigenetic changes in prostate cancer cells vs. normals.
To better understand LRES, the researchers created a prostate cancer epigenome map with data from tiling arrays. With data from patient samples and cell lines, they identified numerous LRES regions. LRESs were larger in samples from patients with metastatic cancer compared to those with localized cancers, suggesting that these areas spread in the genome as the cancer starts to spread in the body.
A careful analysis of the LRESs led to these findings:
- LRES regions had an overall loss of H3K9 acetylation and reduced transcription.
- Epigenetic marks cluster in LRESs, but the particular repressive marks vary.
- The type of epigenetic mod found in cancer-cell LRESs depended on the transcriptional state of that region in normal cells. For example, re-enforcement marks (really low H3K9ac, lots of H3K9me2 and H3K27me3) were found in regions that were suppressed in normal cells, whereas multiple repressive marks (zero H3K9ac, but some H3K27me3 and maybe a lot of H3K9me2 and DNA hypermethylation) showed up in areas that are typically active in normal cells.
- The epigenetic mods in LRES regions didn’t really look like the mods found in human embryonic stem cells, so it doesn’t seem that these cancer cells were reverting to a stem-cell-like state.
The researchers say that a combination of LRES, loss of heterozygosity, and/or deletions lead to less transcriptional flexibility in cancer cells. Check out the full details at Nature, February 2009.