Abstract
The histone modification H3K27me3 plays a central role in Polycomb-mediated epigenetic silencing. H3K27me3 recruits and allosterically activates Polycomb Repressive Complex 2 (PRC2), which adds this modification to nearby histones, providing a read/write mechanism for inheritance through DNA replication. However, for some PRC2 targets, a purely histone-based system for epigenetic inheritance may be insufficient. We address this issue at the Polycomb target FLOWERING LOCUS C (FLC) in Arabidopsis thaliana, as a narrow nucleation region of only ~three nucleosomes within FLC mediates epigenetic state switching and subsequent memory over many cell cycles. To explain the memory's unexpected persistence, we introduce a mathematical model incorporating extra protein memory storage elements with positive feedback that persist at the locus through DNA replication, in addition to histone modifications. Our hybrid model explains many features of epigenetic switching/memory at FLC and encapsulates generic mechanisms that may be widely applicable.
Highlights
The mechanistic basis for epigenetic state switching and memory storage is incompletely understood
We found that incorporating a separate, rapid H3K27me0 to me1 transition in the model that was not catalysed by Polycomb Repressive Complex 2 (PRC2) did not substantially affect our results, as our existing model already led to rapid H3K27me1 recovery
We have developed a full model of epigenetic switching and memory including nucleation and spreading at Arabidopsis thaliana FLOWERING LOCUS C (FLC), significantly extending the conventional H3K27me3 memory element and read/write feedback paradigm
Summary
The mechanistic basis for epigenetic state switching and memory storage is incompletely understood. The enzymatic complex that adds this modification, PRC2, can recognise existing H3K27me and add more methyl groups to nearby histones in a read/write maintenance mechanism (Hansen et al, 2008; Margueron et al, 2009). In this way, targets with existing H3K27me can generate more H3K27me and thereby survive perturbations. The read/ write feedbacks can fill in the missing H3K27me to restore levels similar to those prior to replication In this paradigm, the histone modifications are the only causative memory elements able to store information about silencing through DNA replication. These marks are maintained against losses, including at DNA replication, by the PRC2 enzymatic machinery
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