Gene Regulation mediated by Bivalent Chromatin Domains

Abstract

During recent years technical advances have made it possible to study chromatin modifications at high resolution in homogenous cell populations. This thesis will focus on recent developments in the field of polycomb-mediated gene silencing and its associated prototypical chromatin mark Histone 3 lysine 27 tri-methylation (H3K27me3). Interestingly, vertebrate stem-cell precursor chromatin contains so-called bivalently marked genes which are enriched for both H3K27me3 and the opposing and hence gene activating mark H3K4me3. Bivalent domains are mostly located at silent genes involved in embryogenesis and development and depend on Polycomb Repressive Complexes 2 (PRC2) and 1 (PRC1) to be established and maintenaned. It is hypothesized that bivalency is crucial in either timing or poising of gene transcription once required during embryogenesis. This thesis discusses several lines of research supporting these claims. Also an alternative hypothesis is brought up for the biological relevance of bivalency at specific genes. PRC2 and PRC1 colocalize at a subgroup of bivalent genes. Both complexes are involved in, seemingly, independent pathways leading to RNA Pol II (RNAP) stalling, hence preventing transcriptional elongation to commence. It is therefore that I suggest bivalency ensures a doubled effort in gene repression during crucial developmental stages. Elucidating the function of bivalent domains will help us to understand their role in regulating embryogenesis. Surprisingly, Drosophila, like other non-vertebrates, lacks bivalent chromatin domains, even though homologous target genes, individual chromatin marks and the necessary machineries involved are al present. Hence, it remains to be clarified what role bivalent domains have in vertebrate embryogenesis and eventually how non-vertebrates manage without them.