Zhou Pilot Project Summary

Whole genome duplications (WGD) result in polyploid genomes. Polyploidy can occur within an organism to generate new cell types or during evolution during speciation. New genome sequencing studies have now demonstrated the pervasiveness of polyploidy in cancers, as 30% of all cancers and 56% of metastatic cancers having experienced at least 1 WGD. Polyploidy in cancer is correlated with rapid accumulation of aneuploidy and exacerbated disease outcome, making it an ideal phenotypic target for molecular therapeutics. Yet, we do not have a fundamental understanding of how polyploidy rewires the genome in order to create new genome functions.

In this proposal we aim to use the African clawed frog Xenopus to investigate the direct consequences of polyploidy on 3D genome organization and dynamics. We will take advantage of Xenopus as a highly robust developmental and cell biological model that is also highly amenable to changes in ploidy. We will use Xenopus species that span a 6-fold range in ploidy and artificial ways to manipulate ploidy by 3-fold in Xenopus embryo. In Aim 1, we will examine the consequence of ploidy on the abundance and distribution of maternally loaded epigenetic factors that have important consequences for transcriptional activation in the early embryo. In Aim 2, we will develop a novel live imaging approach to visualize the dynamics of chromatin domains in embryos with different ploidies. Together, the results of these aims will provide a mechanistic and comprehensive understanding of how polyploidy reorganizes the epigenome to regulate transcriptional output during early development and across evolution.