Life Sciences Research for Lifelong Health

Jon Houseley

Research Summary

Our research aim is to uncover the causes and consequences of genome change. We tend to think of genomes as long-term stable repositories of information, providing all the information required to produce an organism. However, genomes can change, and not just over evolutionary timescales. Genome changes are a hallmark of cancer, but it is increasingly clear that some genetic loci are very prone to change in healthy cells during the lifespan of various organisms. 

The causes and consequences of these genome changes are poorly understood; we aim to understand why and how genetic information changes and to what extent these changes are regulated. Our work addresses the relationship between gene expression patterns, epigenetic marks and genetic changes that define the interactions of cells with their environment.

Jon is a Wellcome Trust Senior Research Fellow.

Latest Publications

Gene expression hallmarks of cellular ageing.
Frenk S, Houseley J

Ageing leads to dramatic changes in the physiology of many different tissues resulting in a spectrum of pathology. Nonetheless, many lines of evidence suggest that ageing is driven by highly conserved cell intrinsic processes, and a set of unifying hallmarks of ageing has been defined. Here, we survey reports of age-linked changes in basal gene expression across eukaryotes from yeast to human and identify six gene expression hallmarks of cellular ageing: downregulation of genes encoding mitochondrial proteins; downregulation of the protein synthesis machinery; dysregulation of immune system genes; reduced growth factor signalling; constitutive responses to stress and DNA damage; dysregulation of gene expression and mRNA processing. These encompass widely reported features of ageing such as increased senescence and inflammation, reduced electron transport chain activity and reduced ribosome synthesis, but also reveal a surprising lack of gene expression responses to known age-linked cellular stresses. We discuss how the existence of conserved transcriptomic hallmarks relates to genome-wide epigenetic differences underlying ageing clocks, and how the changing transcriptome results in proteomic alterations where data is available and to variations in cell physiology characteristic of ageing. Identification of gene expression events that occur during ageing across distant organisms should be informative as to conserved underlying mechanisms of ageing, and provide additional biomarkers to assess the effects of diet and other environmental factors on the rate of ageing.

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Biogerontology, , 1573-6768, , 2018

PMID: 29492790

Can aging be beneficial?
Frenk S, Houseley J

Aging, , 1945-4589, , 2017

PMID: 29074820

Environmental change drives accelerated adaptation through stimulated copy number variation.
Hull RM, Cruz C, Jack CV, Houseley J

Copy number variation (CNV) is rife in eukaryotic genomes and has been implicated in many human disorders, particularly cancer, in which CNV promotes both tumorigenesis and chemotherapy resistance. CNVs are considered random mutations but often arise through replication defects; transcription can interfere with replication fork progression and stability, leading to increased mutation rates at highly transcribed loci. Here we investigate whether inducible promoters can stimulate CNV to yield reproducible, environment-specific genetic changes. We propose a general mechanism for environmentally-stimulated CNV and validate this mechanism for the emergence of copper resistance in budding yeast. By analysing a large cohort of individual cells, we directly demonstrate that CNV of the copper-resistance gene CUP1 is stimulated by environmental copper. CNV stimulation accelerates the formation of novel alleles conferring enhanced copper resistance, such that copper exposure actively drives adaptation to copper-rich environments. Furthermore, quantification of CNV in individual cells reveals remarkable allele selectivity in the rate at which specific environments stimulate CNV. We define the key mechanistic elements underlying this selectivity, demonstrating that CNV is regulated by both promoter activity and acetylation of histone H3 lysine 56 (H3K56ac) and that H3K56ac is required for CUP1 CNV and efficient copper adaptation. Stimulated CNV is not limited to high-copy CUP1 repeat arrays, as we find that H3K56ac also regulates CNV in 3 copy arrays of CUP1 or SFA1 genes. The impact of transcription on DNA damage is well understood, but our research reveals that this apparently problematic association forms a pathway by which mutations can be directed to particular loci in particular environments and furthermore that this mutagenic process can be regulated through histone acetylation. Stimulated CNV therefore represents an unanticipated and remarkably controllable pathway facilitating organismal adaptation to new environments.

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PLoS biology, 15, 1545-7885, e2001333, 2017

PMID: 28654659

Group Members

Latest Publications

Gene expression hallmarks of cellular ageing.

Frenk S, Houseley J

1573-6768: (2018)

PMID: 29492790

Can aging be beneficial?

Frenk S, Houseley J

1945-4589: (2017)

PMID: 29074820

Environmental change drives accelerated adaptation through stimulated copy number variation.

Hull RM, Cruz C, Jack CV

PLoS biology
15 1545-7885:e2001333 (2017)

PMID: 28654659

RNA binding by the histone methyltransferases Set1 and Set2.

Sayou C, Millán-Zambrano G, Santos-Rosa H

Molecular and cellular biology
1098-5549: (2017)

PMID: 28483910

Multi-tissue DNA methylation age predictor in mouse.

Stubbs TM, Bonder MJ, Stark AK

Genome biology
18 1474-760X:68 (2017)

PMID: 28399939

Aging yeast gain a competitive advantage on non-optimal carbon sources.

Frenk S, Pizza G, Walker RV

Aging cell
1474-9726: (2017)

PMID: 28247585

TET-dependent regulation of retrotransposable elements in mouse embryonic stem cells.

de la Rica L, Deniz Ö, Cheng KC

Genome biology
17 1474-760X:234 (2016)

PMID: 27863519

Regulation of ribosomal DNA amplification by the TOR pathway.

Jack CV, Cruz C, Hull RM

Proceedings of the National Academy of Sciences of the United States of America
112 1091-6490:9674-9 (2015)

PMID: 26195783

Unexpected DNA loss mediated by the DNA binding activity of ribonuclease A.

Donà F, Houseley J

PloS one
9 1932-6203:e115008 (2014)

PMID: 25502562

The nuclear exosome is active and important during budding yeast meiosis.

Frenk S, Oxley D, Houseley J

PloS one
9 1932-6203:e107648 (2014)

PMID: 25210768

Endogenous RNA interference is driven by copy number.

C Cruz, J Houseley

3 :e01581 (2014)

PMID: 24520161