Martin Howard

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.

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Latest Publications

Hybrid protein assembly-histone modification mechanism for PRC2-based epigenetic switching and memory.
Lövkvist C, Mikulski P, Reeck S, Hartley M, Dean C, Howard M

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.

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eLife, 10, 1, 02 09 2021

PMID: 34473050

Noncoding SNPs influence a distinct phase of Polycomb silencing to destabilize long-term epigenetic memory at .
Qüesta JI, Antoniou-Kourounioti RL, Rosa S, Li P, Duncan S, Whittaker C, Howard M, Dean C

In , the cold-induced epigenetic regulation of () involves distinct phases of Polycomb repressive complex 2 (PRC2) silencing. During cold, a PHD-PRC2 complex metastably and digitally nucleates H3K27me3 within On return to warm, PHD-PRC2 spreads across the locus delivering H3K27me3 to maintain long-term silencing. Here, we studied natural variation in this process in accessions, exploring Lov-1, which shows reactivation on return to warm, a feature characteristic of in perennial This analysis identifies an additional phase in this Polycomb silencing mechanism downstream from H3K27me3 spreading. In this long-term silencing (perpetuated) phase, the PHD proteins are lost from the nucleation region and silencing is likely maintained by the read-write feedbacks associated with H3K27me3. A combination of noncoding SNPs in the nucleation region mediates instability in this long-term silencing phase with the result that Lov-1 frequently digitally reactivates in individual cells, with a probability that diminishes with increasing cold duration. We propose that this decrease in reactivation probability is due to reduced DNA replication after flowering. Overall, this work defines an additional phase in the Polycomb mechanism instrumental in natural variation of silencing, and provides avenues to dissect broader evolutionary changes at .

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Genes & development, 34, 5-6, 01 03 2020

DOI: 10.1101/gad.333245.119

PMID: 32001513

Open Access

Distinct phases of Polycomb silencing to hold epigenetic memory of cold in .
Yang H, Berry S, Olsson TSG, Hartley M, Howard M, Dean C

Gene silencing by Polycomb complexes is central to eukaryotic development. Cold-induced epigenetic repression of () in the plant provides an opportunity to study initiation and maintenance of Polycomb silencing. Here, we show that a subset of Polycomb repressive complex 2 factors nucleate silencing in a small region within , locally increasing H3K27me3 levels. This nucleation confers a silenced state that is metastably inherited, with memory held in the local chromatin. Metastable memory is then converted to stable epigenetic silencing through separate Polycomb factors, which spread across the locus after cold to enlarge the domain that contains H3K27me3. Polycomb silencing at thus has mechanistically distinct phases, which involve specialization of distinct Polycomb components to deliver first metastable then long-term epigenetic silencing.

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Science (New York, N.Y.), 357, 6356, 15 09 2017

DOI: 10.1126/science.aan1121

PMID: 28818969