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

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

Aging yeast gain a competitive advantage on non-optimal carbon sources.
Frenk S, Pizza G, Walker RV, Houseley J

Animals, plants and fungi undergo an aging process with remarkable physiological and molecular similarities, suggesting that aging has long been a fact of life for eukaryotes and one to which our unicellular ancestors were subject. Key biochemical pathways that impact longevity evolved prior to multicellularity, and the interactions between these pathways and the aging process therefore emerged in ancient single-celled eukaryotes. Nevertheless, we do not fully understand how aging impacts the fitness of unicellular organisms, and whether such cells gain a benefit from modulating rather than simply suppressing the aging process. We hypothesized that age-related loss of fitness in single-celled eukaryotes may be counterbalanced, partly or wholly, by a transition from a specialist to a generalist life-history strategy that enhances adaptability to other environments. We tested this hypothesis in budding yeast using competition assays and found that while young cells are more successful in glucose, highly aged cells outcompete young cells on other carbon sources such as galactose. This occurs because aged yeast divide faster than young cells in galactose, reversing the normal association between age and fitness. The impact of aging on single-celled organisms is therefore complex and may be regulated in ways that anticipate changing nutrient availability. We propose that pathways connecting nutrient availability with aging arose in unicellular eukaryotes to capitalize on age-linked diversity in growth strategy and that individual cells in higher eukaryotes may similarly diversify during aging to the detriment of the organism as a whole.

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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, 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

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Keywords

ageing
copy number
epigenetics
genome
variation

Group Members

Latest Publications

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

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

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