Somatic transposition-mediated genome variegation during development, disease and aging conditions

Carnegie Institution Of Washington, D.C., Washington DC

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Abstract

? DESCRIPTION (provided by applicant): Making up almost half of the human genome, transposons are the most abundant residents in almost all animal genomes. These presumed selfish junk DNA sequences represent a potential mutagenic source able to wreak havoc on genome stability and integrity. While a significant amount of research work has shown that germ cells exploit a germline specific small RNA system, the piRNA pathway, to silence transposons in animal gonads, we know surprisingly little about transposon activity and the mechanisms that control transposons in somatic tissues. It has long been assumed that transposons barely move in somatic cells. This conclusion could largely be due to the insensitive tools that have been used to measure transposon mobilization. Recently, increasing evidence suggests that transposition occurs during normal neurogenesis and embryogenesis. Our preliminary data suggest that there are comparable numbers of insertion events in somatic tissues and ovaries during fruit fly development. Interestingly, it has been documented that transposons become highly active in aged cells, following environmental stress or during tumorigenesis. These observations raise the intriguing possibility that transposons contribute to animal development, aging and disease progression. To test this hypothesis, I will first establish a robust platform to capture single transposition events with single cell resolution and determine their insertion sites with base-pair resolution (aim 1). Based on the encouraging preliminary data we have, in the second aim, I will apply our platform to study transposon activities in astrocytes and explore potential functions of transposons in these most abundant brain cells. To understand mechanisms that underlie transposon control in somatic tissue, I will also perform a genome wide mutagenesis screen to identify the components that are required to tame transposons. In the third aim, I will focus on the transposon activities during aging, which is a primary factor fo many devastating diseases, and examine the potential impacts of transposons on aging and aging-associated disease. Collectively, these studies develop new tools to study transposon activity and potential function, characterize new paradigms to understand animal development, aging and disease progression, and potentially provide new perspective to treat diseases by harnessing transposons.