Houseley Group

Houseley Group
Houseley Group
Jon Houseley
Group Leader and Head of Knowledge Exchange & Commercialisation
Houseley Group

Research Summary

We study the mechanisms by which cells learn to thrive in new environments.
From yeast caught by the wind and scattered across the landscape or plankton dwelling in increasingly acidified oceans to malignant cells facing modern targeted anticancer drugs, cells often face a stark choice – adapt or die.
We study the mechanisms by which cells adapt to new environments. A major focus is the unexpected ability of cells to change specific parts of their genomes in response to particular environments. The ability to stimulate mutation at the right time and place is likely to allow organisms to evolve and adapt much faster than we might expect, and such mechanisms have clear medical importance.
Attempting adaptive change is dangerous for any organism, and must be tightly controlled within the life cycle. We are starting to discover connections between adaptation and ageing; we have found that cellular ageing can facilitate adaptation, and conversely we see evidence that the drive to adapt to the environment seems to impact the ageing process.
Jon is a Wellcome Trust Senior Research Fellow.

Latest Publications

Nunes C, Depestel L, Mus L, Keller KM, Delhaye L, Louwagie A, Rishfi M, Whale A, Kara N, Andrews SR, Dela Cruz F, You D, Siddiquee A, Cologna CT, De Craemer S, Dolman E, Bartenhagen C, De Vloed F, Sanders E, Eggermont A, Bekaert SL, Van Loocke W, Bek JW, Dewyn G, Loontiens S, Van Isterdael G, Decaesteker B, Tilleman L, Van Nieuwerburgh F, Vermeirssen V, Van Neste C, Ghesquiere B, Goossens S, Eyckerman S, De Preter K, Fischer M, Houseley J, Molenaar J, De Wilde B, Roberts SS, Durinck K, Speleman F Epigenetics, Bioinformatics

High-risk neuroblastoma, a pediatric tumor originating from the sympathetic nervous system, has a low mutation load but highly recurrent somatic DNA copy number variants. Previously, segmental gains and/or amplifications allowed identification of drivers for neuroblastoma development. Using this approach, combined with gene dosage impact on expression and survival, we identified ribonucleotide reductase subunit M2 (RRM2) as a candidate dependency factor further supported by growth inhibition upon in vitro knockdown and accelerated tumor formation in a neuroblastoma zebrafish model coexpressing human RRM2 with MYCN. Forced RRM2 induction alleviates excessive replicative stress induced by CHK1 inhibition, while high RRM2 expression in human neuroblastomas correlates with high CHK1 activity. MYCN-driven zebrafish tumors with RRM2 co-overexpression exhibit differentially expressed DNA repair genes in keeping with enhanced ATR-CHK1 signaling activity. In vitro, RRM2 inhibition enhances intrinsic replication stress checkpoint addiction. Last, combinatorial RRM2-CHK1 inhibition acts synergistic in high-risk neuroblastoma cell lines and patient-derived xenograft models, illustrating the therapeutic potential.

+view abstract Science advances, PMID: 35857500 15 Jul 2022

Whale AJ, King M, Hull RM, Krueger F, Houseley J Epigenetics

Adaptive mutations can cause drug resistance in cancers and pathogens, and increase the tolerance of agricultural pests and diseases to chemical treatment. When and how adaptive mutations form is often hard to discern, but we have shown that adaptive copy number amplification of the copper resistance gene CUP1 occurs in response to environmental copper due to CUP1 transcriptional activation. Here we dissect the mechanism by which CUP1 transcription in budding yeast stimulates copy number variation (CNV). We show that transcriptionally stimulated CNV requires TREX-2 and Mediator, such that cells lacking TREX-2 or Mediator respond normally to copper but cannot acquire increased resistance. Mediator and TREX-2 can cause replication stress by tethering transcribed loci to nuclear pores, a process known as gene gating, and transcription at the CUP1 locus causes a TREX-2-dependent accumulation of replication forks indicative of replication fork stalling. TREX-2-dependent CUP1 gene amplification occurs by a Rad52 and Rad51-mediated homologous recombination mechanism that is enhanced by histone H3K56 acetylation and repressed by Pol32 and Pif1. CUP1 amplification is also critically dependent on late-firing replication origins present in the CUP1 repeats, and mutations that remove or inactivate these origins strongly suppress the acquisition of copper resistance. We propose that replicative stress imposed by nuclear pore association causes replication bubbles from these origins to collapse soon after activation, leaving a tract of H3K56-acetylated chromatin that promotes secondary recombination events during elongation after replication fork re-start events. The capacity for inefficient replication origins to promote copy number variation renders certain genomic regions more fragile than others, and therefore more likely to undergo adaptive evolution through de novo gene amplification.

+view abstract Nucleic acids research, PMID: 35018465 08 Jan 2022

Kara N, Krueger F, Rugg-Gunn P, Houseley J Epigenetics, Bioinformatics

Faithful replication of the entire genome requires replication forks to copy large contiguous tracts of DNA, and sites of persistent replication fork stalling present a major threat to genome stability. Understanding the distribution of sites at which replication forks stall, and the ensuing fork processing events, requires genome-wide methods that profile replication fork position and the formation of recombinogenic DNA ends. Here, we describe Transferase-Activated End Ligation sequencing (TrAEL-seq), a method that captures single-stranded DNA 3' ends genome-wide and with base pair resolution. TrAEL-seq labels both DNA breaks and replication forks, providing genome-wide maps of replication fork progression and fork stalling sites in yeast and mammalian cells. Replication maps are similar to those obtained by Okazaki fragment sequencing; however, TrAEL-seq is performed on asynchronous populations of wild-type cells without incorporation of labels, cell sorting, or biochemical purification of replication intermediates, rendering TrAEL-seq far simpler and more widely applicable than existing replication fork direction profiling methods. The specificity of TrAEL-seq for DNA 3' ends also allows accurate detection of double-strand break sites after the initiation of DNA end resection, which we demonstrate by genome-wide mapping of meiotic double-strand break hotspots in a dmc1Δ mutant that is competent for end resection but not strand invasion. Overall, TrAEL-seq provides a flexible and robust methodology with high sensitivity and resolution for studying DNA replication and repair, which will be of significant use in determining mechanisms of genome instability.

+view abstract PLoS biology, PMID: 33760805 24 Mar 2021

bioRxiv Manuscripts

Prasanna Channathodiyil, Anne Segonds-Pichon, Paul D. Smith, Simon J. Cook, Jonathan Houseley
bioRxiv 2021.03.23.436572

Alex J. Whale, Michelle King, Ryan M. Hull, Felix Krueger, Jonathan Houseley
bioRxiv 2021.03.04.433911

Group Members

Jon Houseley

Group Leader and Head of Knowledge Exchange & Commercialisation

Hanane Hadj-Moussa

Postdoc Research Scientist

Dorottya Horkai

Visiting Scientist

Neesha Kara

PhD Student

Kieron May

PhD Student

Alex Whale

Postdoc Research Scientist