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

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

RNA binding by the histone methyltransferases Set1 and Set2.
Sayou C, Millán-Zambrano G, Santos-Rosa H, Petfalski E, Robson S, Houseley J, Kouzarides T, Tollervey D

Histone methylation at H3K4 and H3K36 is commonly associated with genes actively transcribed by RNA polymerase II (RNAPII) and is catalyzed by yeast Set1 and Set2, respectively. Here we report that both methyltransferases can be UV-crosslinked to RNA in vivo. High-throughput sequencing of the bound RNAs revealed strong Set1 enrichment near the transcription start site, whereas Set2 was distributed along pre-mRNAs. A subset of transcripts showed notably high enrichment for Set1 or Set2 binding relative to RNAPII, suggesting functional post-transcriptional interactions. In particular, Set1 was strongly bound to the SET1 mRNA, Ty1 retrotransposons, and non-coding RNAs from the rDNA intergenic spacers, consistent with its previously reported silencing roles. Set1 lacking RRM2 showed reduced in vivo crosslinking to RNA and reduced chromatin occupancy. In addition, levels of H3K4 tri-methylation were decreased whereas di-methylation was increased. We conclude that RNA binding by Set1 contributes to both chromatin association and methyltransferase activity.

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Molecular and cellular biology, , 1098-5549, , 2017

PMID: 28483910

Group Members

Latest Publications

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

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

eLife
3 :e01581 (2014)

PMID: 24520161

Etoposide Induces Nuclear Re-Localisation of AID.

LJ Lambert, S Walker, J Feltham

PloS one
8 12:e82110 (2013)

DOI: 10.1371/journal.pone.0082110

PMID: 24324754