It’s usually not hard to spot when things seem like they’re destined for failure. Like you ne’er do well cousin, or an American car from the 80’s. Other times, closer examination is required to find the seeds of a problem. That’s what it took for scientists to uncover how some harmless embryonic stem cells (ESCs) are programmed to become deadly cancer cells later on.
The European research team, headed up by Manel Esteller, took a systematic approach to understanding the underlying epigenetic mechanisms in oncogenesis.
- First, genomic bisulfite sequencing revealed that miRNA tumor suppressor genes (like miR-9, miR-124a1, miR-148a, miR-34b and miR-34c) are hypermethylated in cancer, yet unmethylated in stem cells.
- Next, qRT-PCR assays showed that those same miRNA genes were only minimally expressed in ESCs. Obviously, something other than CpG promoter methylation was keeping transcription low.
- The scientists then focused on the histone mods H3K9me3, H3K27me3 (both repressive marks) and H3K4me3 (an active mark) in quantitative ChIP experiments. They found that ESCs had both active and repressive, or bivalent marks (H3K4me3/H3K27me3 with or without H3K9me3) in the miRNA promoters, while cancer cells only had repressive marks in those promoter regions.
Adding up all the evidence led the research team to conclude that the specific miRNA genes found to be disregulated in cancers are actually premarked with a special histone code in ESCs. In other words, some stem cells may be “bad apples” before they even differentiate.
Don’t fail to get all the details at Epigenetics, November 2011.