Diseccionando el papel de Polycomb en la regulación de genes bivalentes a través del ciclo celular en células madre embrionarias

Abstract

Embryonic stem cells (ESCs) are endorsed with an indefinite cell division potential while being able to differentiate into all cell types that compose an adult organism. Over the last decade, several studies have suggested that the potential of stem cells to differentiate vary during cell cycle transition, being G1 the phase of the cell cycle in which cells seem to be more prone to enter cell differentiation. Importantly, the molecular mechanisms regulating this cell cycle-dependent differentiation ability are unknown. Polycomb repressor complexes (PRCs) are epigenetic regulators that repress developmental genes in ESCs through the catalysis of histone modifications and supporting three-dimensional (3D) organization of chromatin within the cell nucleus. In this thesis, we demonstrate that the activity of PRCs changes during cell cycle transition, leading to variations in chromatin interactions and gene expression of PRC target developmental genes in mouse ESCs. Recruitment of PRCs to target promoters is particularly enriched during G2 as compared to G1 and S phases and it is coupled to higher 3D chromatin interactions and downregulation of target genes. Genetic ablation of different Polycomb subunits interfere with the cell cycle dependent regulation of chromatin organization and RNA synthesis from target promoters. Thus, I propose that the dynamic activity of PRCs across cell cycle is the basis of an epigenetic cycle that favours a chromatin setup that facilitates pluripotency exit and cell differentiation in G1.