Deciphering temporal order of epigenetic changes during lymphomagenesis

Abstract

Tumorigenesis is a multistep process with normal cells transitioning through an intermediate pre-tumor stage to eventually transform into tumor cells. However, the underlying temporal order of epigenetic changes in these intermediate stages of tumorigenesis is poorly studied. Using the Eμ-Myc mice model of spontaneous B-cell lymphoma, we have dissected into the transcription and DNA methylation changes specifically from the bivalent genes and the ribosomal DNA (rDNA) locus during lymphomagenesis. We report an increase in rDNA transcription with a counterintuitive increased fraction of promoter-methylated rDNA repeats during tumorigenesis. We propose that the increased promoter methylation safeguards a fraction of rDNA repeats from transcription induced damage and promotes cancer cell survival. We report peculiar patterns of gene expression changes in epigenetic modifiers at different stages of tumorigenesis. We also report a characteristic transient increase in the expression of developmental genes from the bivalent promoters despite increased DNA methylation in the early pre-tumor stage of tumorigenesis. Taken together, the novel findings from our study give us interesting insights into the temporal order of epigenetic changes during tumorigenesis.