Investigating the role of Retrotransposon muERV-L reactivation in Tumorigenesis

University Of California Berkeley, Berkeley CA

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Abstract

? DESCRIPTION (provided by applicant): Investigating the role of Retrotransposon muERV-L reactivation in Tumorigenesis. Background: Throughout evolution, ancient foreign nucleic acid sequences have infected and spread throughout the genomes of nearly all organisms. These parasitic elements mobilize in order to rearrange their position and propagate throughout the host genome. 42% of the human genome originates from a class of mobile element called retrotransposons and has evolved elaborate mechanisms to suppress the potentially mutagenic effects of aberrant reactivations. Although exceedingly efficient at silencing retrotransposons, developmental and tissue specific expression patterns of specific retrotransposon families suggest that these elements have been domesticated by their host genomes. Preliminary results demonstrate that during the induction of pluripotent stem cells in the absence of the tumor suppressor p53, the ancient class of mouse retrotransposon, muERV-L is de-repressed while nearly all other retrotransposon silencing remains intact. This reactivation, occurring at thousands of loci, is accompanied by the significant misregulation of gene activity specifically adjacent to muERV-L loci. Whether these effects contribute to or are a consequence of the enhanced tumorigenicity of p53 loss is the focus of this investigation. Hypothesis: Our preliminary studies indicate that upon induction of pluripotent stem cells lacking the tumor suppressor p53, the retrotransposon muERV-L is reactivated with significant impact on neighboring gene activity. Therefore, I hypothesize that p53 mediates muERV-L retrotransposon silencing during tumor development. Specific Aims: (1) Rescue altered gene expression in p53 deficient iPS cells via muERV-L disruption. (2) Characterize aberrant retrotransposon activity in in vivo cancer development. (3) Investigate the mechanism through which p53 represses specific retrotransposons. Study design: The novel CRISPR genome editing technique pioneered here at UC Berkeley will be used to disrupt specific muERV-L loci to assess changes on potential cis regulatory effects. Next, two distinct mouse models of lung cancer will be used to investigate the in vivo effect of muERV-L reactivation on tumor formation. Genetic, biochemical and molecular approaches on p53 deficient cell lines and mouse models will be used to investigate the epigenetic and transcriptional machinery downstream of p53 that confer this sequence-specific regulation for retrotransposon silencing.