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

TET-dependent regulation of retrotransposable elements in mouse embryonic stem cells.
de la Rica L, Deniz Ö, Cheng KC, Todd CD, Cruz C, Houseley J, Branco MR

Ten-eleven translocation (TET) enzymes oxidise DNA methylation as part of an active demethylation pathway. Despite extensive research into the role of TETs in genome regulation, little is known about their effect on transposable elements (TEs), which make up nearly half of the mouse and human genomes. Epigenetic mechanisms controlling TEs have the potential to affect their mobility and to drive the co-adoption of TEs for the benefit of the host.

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Genome biology, 17, 1474-760X, 234, 2016

PMID: 27863519

Regulation of ribosomal DNA amplification by the TOR pathway.
Jack CV, Cruz C, Hull RM, Keller MA, Ralser M, Houseley J

Repeated regions are widespread in eukaryotic genomes, and key functional elements such as the ribosomal DNA tend to be formed of high copy repeated sequences organized in tandem arrays. In general, high copy repeats are remarkably stable, but a number of organisms display rapid ribosomal DNA amplification at specific times or under specific conditions. Here we demonstrate that target of rapamycin (TOR) signaling stimulates ribosomal DNA amplification in budding yeast, linking external nutrient availability to ribosomal DNA copy number. We show that ribosomal DNA amplification is regulated by three histone deacetylases: Sir2, Hst3, and Hst4. These enzymes control homologous recombination-dependent and nonhomologous recombination-dependent amplification pathways that act in concert to mediate rapid, directional ribosomal DNA copy number change. Amplification is completely repressed by rapamycin, an inhibitor of the nutrient-responsive TOR pathway; this effect is separable from growth rate and is mediated directly through Sir2, Hst3, and Hst4. Caloric restriction is known to up-regulate expression of nicotinamidase Pnc1, an enzyme that enhances Sir2, Hst3, and Hst4 activity. In contrast, normal glucose concentrations stretch the ribosome synthesis capacity of cells with low ribosomal DNA copy number, and we find that these cells show a previously unrecognized transcriptional response to caloric excess by reducing PNC1 expression. PNC1 down-regulation forms a key element in the control of ribosomal DNA amplification as overexpression of PNC1 substantially reduces ribosomal DNA amplification rate. Our results reveal how a signaling pathway can orchestrate specific genome changes and demonstrate that the copy number of repetitive DNA can be altered to suit environmental conditions.

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

PMID: 26195783

Annual meeting of the EpiGeneSys Network of Excellence - Advancing epigenetics towards systems biology.
Houseley J, Hill CS, Rugg-Gunn PJ

The third annual meeting of the EpiGeneSys network brought together epigenetics and systems biologists to report on collaborative projects that apply quantitative approaches to understanding complex epigenetic processes. The figure shown represents one meeting highlight, which was the unexpected emergence of genotype versus epigenotype in control of cell state.

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BioEssays, 2015, , , , 2015

PMID: 25776341
DOI: 10.1002/bies.201500015

01223 496113

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Latest Publications

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

Resolution of budding yeast chromosomes using pulsed-field gel electrophoresis.

Hage AE,Houseley J

Methods in molecular biology (Clifton, N.J.)
1054 1940-6029:195-207 (2013)

PMID: 23913294

Form and function of eukaryotic unstable non-coding RNAs.

J Houseley

Biochemical Society transactions
40 4:836-41 (2012)

DOI: 10.1042/BST20120040

PMID: 22817744

The many pathways of RNA degradation.

J Houseley, D Tollervey

Cell
136 4:763-76 (2009)

DOI: 10.1016/j.cell.2009.01.019

PMID: 19239894