Martin is an Honorary Group Leader, currently based at the John Innes Centre. He is working with Group Leaders in the Epigenetics Programme. The Howard group combines simple, predictive mathematical modelling with long-lasting experimental collaborations, to dissect biological mechanisms too complex to unravel by experiments alone. In many cases we are able rationalise complex biological dynamics into simple underlying mechanisms, with few components and interactions.
Our approach is highly interdisciplinary and relies heavily on the techniques of statistical physics and applied mathematics, as well as on close collaboration with experimental groups. This truly interdisciplinary approach allows us to get to the heart of biological mechanisms more speedily.
At present the main focus of the group is epigenetic dynamics, probing how epigenetic memory states are set up and then stably maintained. In this context, we work with both histone modification memory systems, as well as on DNA methylation, collaborating with experimentalists in systems ranging from plants to mammalian stem cells. A particular focus has been the Polycomb epigenetic system, where we have proposed an all-or-nothing epigenetic switching mechanism, with epigenetic gene silencing directly antagonised by transcription. Overall, as epigenetic systems are central to ageing and health, understanding how they work at a fundamental level is of vital importance.
The maintenance of transcriptional states regulated by histone modifications and controlled switching between these states are fundamental concepts in our understanding of nucleosome-mediated epigenetic memory. Any approach relying on genome-wide bioinformatic analyses alone offers limited scope for dissecting the molecular mechanisms involved in maintenance and switching. Mechanistic mathematical models-describing the dynamics of histone modifications at individual genomic loci-offer an alternative way to investigate these mechanisms. These models, in conjunction with quantitative experimental data-ChIP data, quantification of mRNA levels, and single-cell fluorescence tracking in clonal lineages-can generate predictions that drive more targeted experiments, allowing us to understand mechanisms that would be challenging to unravel by a purely experimental approach. In this chapter, we describe a generic stochastic modeling framework that can be used to capture histone modification dynamics and associated molecular processes-including transcription and read-write feedback by chromatin modifying complexes-at individual genomic loci. Using a specific example-transcriptional silencing by Polycomb-mediated H3K27 methylation-we demonstrate how to construct and simulate a stochastic histone modification model. We provide a step-by-step guide to programming simulations for such a model and discuss how to analyze the simulation output.
Epigenetic inheritance of gene expression states enables a single genome to maintain distinct cellular identities. How histone modifications contribute to this process remains unclear. Using global chromatin perturbations and local, time-controlled modulation of transcription, we establish the existence of epigenetic memory of transcriptional activation for genes that can be silenced by the Polycomb group. This property emerges during cell differentiation and allows genes to be stably switched after a transient transcriptional stimulus. This transcriptional memory state at Polycomb targets operates in cis; however, rather than relying solely on read-and-write propagation of histone modifications, the memory is also linked to the strength of activating inputs opposing Polycomb proteins, and therefore varies with the cellular context. Our data and computational simulations suggest a model whereby transcriptional memory arises from double-negative feedback between Polycomb-mediated silencing and active transcription. Transcriptional memory at Polycomb targets thus depends not only on histone modifications but also on the gene-regulatory network and underlying identity of a cell.
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 in , as a narrow nucleation region of only ~three nucleosomes within 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 and encapsulates generic mechanisms that may be widely applicable.