Jon Houseley

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

The adaptive potential of circular DNA accumulation in ageing cells.
Hull RM, Houseley J

Carefully maintained and precisely inherited chromosomal DNA provides long-term genetic stability, but eukaryotic cells facing environmental challenges can benefit from the accumulation of less stable DNA species. Circular DNA molecules lacking centromeres segregate randomly or asymmetrically during cell division, following non-Mendelian inheritance patterns that result in high copy number instability and massive heterogeneity across populations. Such circular DNA species, variously known as extrachromosomal circular DNA (eccDNA), microDNA, double minutes or extrachromosomal DNA (ecDNA), are becoming recognised as a major source of the genetic variation exploited by cancer cells and pathogenic eukaryotes to acquire drug resistance. In budding yeast, circular DNA molecules derived from the ribosomal DNA (ERCs) have been long known to accumulate with age, but it is now clear that aged yeast also accumulate other high-copy protein-coding circular DNAs acquired through both random and environmentally-stimulated recombination processes. Here, we argue that accumulation of circular DNA provides a reservoir of heterogeneous genetic material that can allow rapid adaptation of aged cells to environmental insults, but avoids the negative fitness impacts on normal growth of unsolicited gene amplification in the young population.

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Current genetics, 1, 1, 15 Apr 2020

DOI: 10.1007/s00294-020-01069-9

PMID: 32296868

Transcription-induced formation of extrachromosomal DNA during yeast ageing.
Hull RM, King M, Pizza G, Krueger F, Vergara X, Houseley J

Extrachromosomal circular DNA (eccDNA) facilitates adaptive evolution by allowing rapid and extensive gene copy number variation and is implicated in the pathology of cancer and ageing. Here, we demonstrate that yeast aged under environmental copper accumulate high levels of eccDNA containing the copper-resistance gene CUP1. Transcription of the tandemly repeated CUP1 gene causes CUP1 eccDNA accumulation, which occurs in the absence of phenotypic selection. We have developed a sensitive and quantitative eccDNA sequencing pipeline that reveals CUP1 eccDNA accumulation on copper exposure to be exquisitely site specific, with no other detectable changes across the eccDNA complement. eccDNA forms de novo from the CUP1 locus through processing of DNA double-strand breaks (DSBs) by Sae2, Mre11 and Mus81, and genome-wide analyses show that other protein coding eccDNA species in aged yeast share a similar biogenesis pathway. Although abundant, we find that CUP1 eccDNA does not replicate efficiently, and high-copy numbers in aged cells arise through frequent formation events combined with asymmetric DNA segregation. The transcriptional stimulation of CUP1 eccDNA formation shows that age-linked genetic change varies with transcription pattern, resulting in gene copy number profiles tailored by environment.

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PLoS biology, 17, 12, Dec 2019

DOI: 10.1371/journal.pbio.3000471

PMID: 31794573

Protocols for Northern Analysis of Exosome Substrates and Other Noncoding RNAs.
Cruz C, Houseley J

Over the past decade a plethora of noncoding RNAs (ncRNAs) have been identified, initiating an explosion in RNA research. Although RNA sequencing methods provide unsurpassed insights into ncRNA distribution and expression, detailed information on structure and processing are harder to extract from sequence data. In contrast, northern blotting methods provide uniquely detailed insights into complex RNA populations but are rarely employed outside specialist RNA research groups. Such techniques are generally considered difficult for nonspecialists, which is unfortunate as substantial technical advances in the past few decades have solved the major challenges. Here we present simple, reproducible and highly robust protocols for separating glyoxylated RNA on agarose gels and heat denatured RNA on polyacrylamide-urea gels using standard laboratory electrophoresis equipment. We also provide reliable transfer and hybridization protocols that do not require optimization for most applications. Together, these should allow any molecular biology lab to elucidate the structure and processing of ncRNAs of interest.

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Methods in molecular biology (Clifton, N.J.), 2062, 1, 2020

DOI: 10.1007/978-1-4939-9822-7_5

PMID: 31768973