A model for transmission of the H3K27me3 epigenetic mark

Abstract

Organization of chromatin by epigenetic mechanisms is essential for establishing and maintaining cellular identity in developing and adult organisms. A key question that remains unresolved about this process is how epigenetic marks are transmitted to the next cell generation during cell division. Here we provide a model to explain how trimethylated Lys 27 of histone 3 (H3K27me3), which is catalysed by the EZH2-containing Polycomb Repressive Complex 2 (PRC2), is maintained in proliferating cells. We show that the PRC2 complex binds to the H3K27me3 mark and colocalizes with this mark in G1 phase and with sites of ongoing DNA replication. Efficient binding requires an intact trimeric PRC2 complex containing EZH2, EED and SUZ12, but is independent of the catalytic SET domain of EZH2. Using a heterologous reporter system, we show that transient recruitment of the PRC2 complex to chromatin, upstream of the transcriptional start site, is sufficient to maintain repression through endogenous PRC2 during subsequent cell divisions. Thus, we suggest that once the H3K27me3 is established, it recruits the PRC2 complex to maintain the mark at sites of DNA replication, leading to methylation of H3K27 on the daughter strands during incorporation of newly synthesized histones. This mechanism ensures maintenance of the H3K27me3 epigenetic mark in proliferating cells, not only during DNA replication when histones synthesized de novo are incorporated, but also outside S phase, thereby preserving chromatin structure and transcriptional programs.

Chromatin computation: Epigenetic inheritance as a pattern reconstruction problem

“…Several models for histone segregation and depositioning have been proposed in the last years, and due to the crucial importance of replication for any chromatin-based inheritance, a few of them will be presented in some detail in the following. The random or conservative model assumes that parental histones are deposited randomly between both strands while the gaps are filled with newly assembled and unmodified nucleosomes (Jackson and Chalkley, 1985;Corpet and Almouzni, 2009;Hansen et al, 2008). Thus, at any position in each of the strands, the probability that parental histones are incorporated is 50% (Figure 2 D).…”

The Epigenetic Landscape of Lineage Choice: Lessons From the Heritability of Cd4 and Cd8 Expression

“…Strictly speaking, epigenetic marks are not contained in the primary genetic sequence, but are stable and heritable even in the absence of their sequence-specific initiating events. For example, H3K27 trimethylation, is both catalyzed and recognized by the PRC2 methyltransferase complex (Hansen et al, 2008). The PRC2 subunit, EED, binds H3K27me3 both to recruit the PRC2 complex and to allosterically activate its methyltransferase activity, setting up a positive feedback loop to propagate the epigenetic mark through cell division without need for sequence specific factors (Margueron et al, 2009).…”

Nucleosome assembly and epigenetic inheritance

“…Another example is the self propagation of H3K27me3, a mark catalyzed by polycomb group protein PRC2, which is known as a regulator of cell memory (Schwartz and Pirrotta, 2007). Recently, using a reporter system in cultured human cells, Hansen et al (2008) showed that H3K27me3 mediated gene silencing, once established, can be maintained independent of genetic elements through several cell divisions. They also found an in vitro binding between PRC2 and H3 tail trimethylated on lysine 27 (Hansen et al, 2008), which provides a possible explanation for the in vivo self maintenance.…”

“…Recently, using a reporter system in cultured human cells, Hansen et al (2008) showed that H3K27me3 mediated gene silencing, once established, can be maintained independent of genetic elements through several cell divisions. They also found an in vitro binding between PRC2 and H3 tail trimethylated on lysine 27 (Hansen et al, 2008), which provides a possible explanation for the in vivo self maintenance. Combining structural biology, biochemistry and Drosophila genetics, Margueron et al (2009) showed the potential mechanism of H3K27me3 transmission from mother cells to daughter cells.…”