Poster Presentation Epigenetics 2013

Alternative Lengthening of Telomeres (ALT) in Human Placenta: First Evidence for ALT in Non-Cancerous Human Tissue (#201)

Boris Novakovic 1 , Christine Napier 2 , Roger Reddel 1 , Jeffrey Craig 1 , Richard Saffery 1
  1. Murdoch Childrens Research Institute, Parkville, VIC, Australia
  2. Children's Medical Research Institute, Westmead, NSW, Australia
The human placenta facilitates the interaction between the mother and the developing foetus during pregnancy. Major roles include nutrient, gas and waste exchange, as well as modulation of the maternal immune response. The process of placentation shows striking similarities to tumourogenesis, including growth in low oxygen, invasion of maternal decidua and remodelling of maternal blood vessels. Likewise, the human placental epigenome shares several features with human cancers, including low global methylation, partially methylated domains (PMDs) and tumour suppressor methylation. Another interesting feature of the placenta is long telomeres. Telomeres are repetitive sequences (TTAGGGn) at the end of each chromosome, and in healthy somatic cells telomeres become shorter after each cell division, eventually leading to cell death. Cancer cells prevent telomere shortening by employing telomere maintenance mechanisms, with 85% of cancers utilising the telomerase complex, and the other 15% using an alternative lengthening of telomeres (ALT) mechanism.  Due to the presence of long telomeres in human placenta in the absence of strong telomerase activity, we hypothesise that the human placenta utilises ALT to maintain telomere length. Therefore we predict that the human placenta would share the unique epigenetic features associated with ALT cancers. These include: (1) telomere recombination between chromosomes (2) high expression of telomere repeat containing RNA (TERRA) and (3) TERRA CpG Island promoter hypomethylation. We report placenta-specific genome-wide hypomethylation at TERRA promoters with an associated high expression of TERRA. Furthermore, our data suggest that telomere recombination (ALT mechanism) is common in the highly proliferative first trimester placenta, but not in terminally differentiated full term placenta. This is the first report of the ALT mechanism in a human tissue other than cancer. Mouse studies suggest ALT may be a common phenomenon in somatic cells, and further study in the placenta may provide clues to the evolution of ALT in mammals.