WIMM PI
Curriculum Vitae
Personal Data
Name
Nationality
Email
Jim Hughes
UK
jim.hughes@imm.ox.ac.uk
Present Position
2012-present
Group Leader, Hughes Genome Biology Group, (MHU, University of
Oxford)
2014-present
Associate Professor of Genome Biology, (University of Oxford)
Previous Positions
1992
Research Assistant (University of Oxford)
1995
DPhil. Student (University of Oxford)
1999
Postdoctoral Researcher (University of Oxford)
2001
Postdoctoral Researcher (MRC)
2003
Investigating Scientist (MRC)
Research Achievements
In the “pre-genome” era I played a key role in identifying disease genes such as PKD1
(responsible for adult dominant polycystic kidney disease), TSC2 (responsible for tuberous
sclerosis type 2) and several other functionally related genes. To understand the function of
the genes and its disrupted in disease, I created the first transgenic mouse models of PKD.
In addition to these classical Molecular Medicine approaches, I was one of the first biologists
to develop relevant skills in bioinformatics. This background has given me an extremely
broad grounding in molecular biology, genetics, scientific method and emphasised the
necessity of developing a high level of computation competence in clinically important
aspects of biology.
From identification of disease genes the focus of my research has shifted to the regulation of
gene expression. I joined the Higgs laboratory in 2000 and since that time have played a
major role in studying globin gene expression as a paradigm of transcriptional regulation.
Subsequently, with an accessible cell system (erythropoiesis) and a well characterised
e genes forward to
contribute to our understanding of the principles of gene expression genome-wide. The
ability to detect genome-wide enrichment now by sequencing has revolutionised our ability
to interrogate genome biology, however, the ability to use these methods effectively requires
a high level of computational expertise, which I played a large contributing role in Oxford due
to my experience and skills.
As computational approaches to molecular medicine have become a central part of the
WIMM’s future vision, in 2012 I was asked to lead a new group, as an independent PI in the
Weatherall Institute of Molecular Medicine with the remit of developing genome-scale
approaches to investigate nuclear function and was appointed the Associate Professor of
Genome Biology in 2014.
What are the Future Aims of Your Current Group?
The Hughes Group is expert in the generation and analysis of genome-wide data, such as
ChIP-seq, DNase-seq and RNA-seq, but also develops novel approaches to interrogate
inaccessible aspects of genome biology. The group is an unusual blend of bench science
and computational analysis that underlies its facility for creating novel NGS based assays to
address currently difficult questions in genome function. The questions the group are
interested in relate to the biology of the distal regulatory elements of genes. It has become
increasingly clear that these elements are central to the existence of complex multicellular
organisms, as they control the differentiation and development of specialised tissues. It is
also clear that sequence changes in these elements are a major factor in health and disease
in the human population. However, in contrast to this importance very little is known about
how these elements function mechanistically and this is in part is due to their unpredictable
distribution in the genome around the genes the control. The group developed a method
(Capture-C) to overcome this major bottleneck in the field allowing the linking of regulatory
elements to the genes they control en mass. We are in the process of exploiting this ability
to investigate in detail the molecular processes of how these elements control their target
promoters. In particular having linked the regulatory and promoter elements we are now
using high-resolution approaches to map protein binding events as the regulatory elements
switch on during development to determine the relationship between this and transcriptional
enhancement of the promoter. For comparative analysis we also study these events at
regulatory elements have been deleted or in
mouse strains where they are disrupted by SNPs, to see which activities are affected by the
loss of these elements.
How do These Aims Contribute to the Understanding and/or Management of Human
Disease
Distal regulatory elements are now known to be ubiquitously involved in all aspects of
molecular medicine as the medium through which transcription factors exert their effect.
Hence, a better understanding of their function will contribute to diverse fields of research
within the WIMM and beyond. Distal regulatory elements undoubtedly play a central role in
processes such as stem cell commitment, cancer genomics, immune response,
haematopoietic and immunological development hence methodological and biological
advances from our work will feed directly into these fields of research within the WIMM. The
most immediate translational benefit comes from the interpretation of sequence variants
within these elements in human disease in two clinical fields. The first is the interpretation
of genome-wide association studies (GWAS) signals where human variants are associated
with increased risk of disease within the normal population.
It has become clear that the
large majority of changes identified in GWAS studies are not associated with genes and are
in fact located large distances from them implying a link with distal regulatory elements. It
has therefore become clear to the GWAS field that the expertise and methodology developed
in research into distal regulatory elements has clear and immediate use in dissecting GWAS
signals and to that end the group is centrally involved in several strategic initiatives to
promote this cross fertilization of fields. By extension this observation also holds true for
clinical genetics as mutations which affect distal regulatory elements have typically be
impossible to ascertain or interpret with any degree of robustness. We are at present setting
up collaborations and transfer of expertise to clinical genetics groups within the WIMM to
investigate the potential for this type of analysis in mutation detection in patients where whole
exome or even whole genome sequencing has not revealed a candidate coding or splicing
mutation.
Lay Summary of Research
The genes in the genome are turned from DNA into RNA which are ultimately turned into the
proteins that forms the cells in our body. As complex multicellular organisms each specialist
cell type requires specific sets of proteins to carry out its specialist function. Specialised
proteins called transcription factors actually control the production and maturation of these
specialist cell types so ultimately which gene gets turned on directs what type of cell a cell
turns into and what the function of that cell will be. It has been found that the regions the
transcription factors proteins bind to and control the activity of a gene can be very far away
from the gene in the genome and even mixed in among other unrelated genes so it is hard to
find all of the things that control the correct program for a gene. This is important medically
because changes in the DNA sequence of these regions can effect how the transcription
factor proteins bind and that can effect how the gene gets turned on, either at the wrong time
or at the wrong level. In the worst case this can cause a disease or in terms of the general
population is means certain people can be susceptible to a large range of conditions such
heart attacks, diabetes or cancer.
Our group studies how these important regulatory
elements function and have produced methods to address the difficult question of how to find
and link regulatory regions to the genes they control. We also use this data to look to see
how sequences changes in these regions can affect the activity of genes and cause or
predispose to certain diseases.
All Publications Over the Past 5 Years
Jim R Hughes, Nigel Roberts, Simon McGowan, Deborah Hay, Eleni Giannoulatou, Magnus
Lynch, Marco De Gobbi, Stephen Taylor, Richard Gibbons, Douglas R Higgs. Analysis of
hundreds of cis-regulatory landscapes at high resolution in a single, high-throughput
experiment. . Nature Genetics 01/2014; • 35.21 Impact Factor
Bryony J Graham, Deborah Hay, Jim Hughes, Doug Higgs. The worm has turned:
Unexpected similarities between the transcription of enhancers and promoters in the worm
and mammalian genomes. BioEssays (2013) 5.42 Impact Factor
Ana C Marques, Jim Hughes, Bryony Graham, Monika S Kowalczyk, Doug R Higgs, Chris P
Ponting. Chromatin signatures at transcriptional start sites separate two equally populated
yet distinct classes of intergenic long noncoding RNAs. Genome biology (2013) 10.30
Impact Factor
Mona Hosseini, Leo Goodstadt, Jim R Hughes, Monika S Kowalczyk, Marco de Gobbi,
Georg W Otto, Richard R Copley, Richard Mott, Douglas R Higgs, Jonathan Flint. Causes
and Consequences of Chromatin Variation between Inbred Mice. PLoS Genetics (2013)
8.52 Impact Factor
Karen M Lower, Marco De Gobbi, Jim R Hughes, Christopher J Derry, Helena Ayyub,
Jacqueline A Sloane-Stanley, Douglas Vernimmen, David Garrick, Richard J Gibbons,
Douglas R Higgs. Analysis of Sequence Variation Underlying Tissue-specific Transcription
Factor Binding and Gene Expression. Human Mutation (2013) 5.21 Impact Factor
Stephen R F Twigg, Elena Vorgia, Simon J McGowan, Ioanna Peraki, Aimée L Fenwick,
Vikram P Sharma, Maryline Allegra, Andreas Zaragkoulias, Elham Sadighi Akha, Samantha
J L Knight, Louise C Wilson, Chris Healy, Paul T Sharpe, Peter Hammond, Jim Hughes,
Stephen Taylor, David Johnson, Steven A Wall, George Mavrothalassitis, Andrew O M
Wilkie. Reduced dosage of ERF causes complex craniosynostosis in humans and mice and
links ERK1/2 signaling to regulation of osteogenesis. Nature Genetics 01/2013; • 35.21
Impact Factor
Jim R Hughes, Karen M Lower, Ian Dunham, Stephen Taylor, Marco De Gobbi, Jacqueline
A Sloane-Stanley, Simon McGowan, Jiannis Ragoussis, Douglas Vernimmen, Richard J
Gibbons, Douglas R Higgs. High-resolution analysis of cis-acting regulatory networks at the
α-globin locus. Philosophical Transactions of The Royal Society B Biological Sciences
(2013) 6.23 Impact Factor
Simon J McGowan, Jim R Hughes, Zong-Pei Han, Stephen Taylor. MIG: Multi-Image
Genome Viewer. Bioinformatics (2013) 5.47 Impact Factor
Kowalczyk MS, Hughes JR, Babbs C, Sanchez-Pulido L, Szumska D, Sharpe JA, SloaneStanley JA, Morriss-Kay GM, Smoot LB, Roberts AE, Watkins H, Bhattacharya S, Gibbons
RJ, Ponting CP, Wood WG, Higgs DR. Nprl3 is required for normal development of the
cardiovascular system. Mamm Genome. 2012 Apr 27.
Hughes JR and Kowalczyk MS, Garrick D and Lynch MD, Sharpe JA, Sloane-Stanley JA,
McGowan SJ, De Gobbi M, Hosseini M, Vernimmen D, Brown JM, Gray NE, Collavin L,
Gibbons RJ, Flint J, Taylor S, Buckle VJ, Milne TA, Wood WG, Higgs DR. Intragenic
enhancers act as alternative promoters. (2012) Mol Cell. 45(4):4 47-58
Lynch MD, Smith AJ, De Gobbi M, Flenley M, Hughes JR, Vernimmen D, Ayyub H, Sharpe
JA, Sloane-Stanley JA, Sutherland L, Meek S, Burdon T, Gibbons RJ, Garrick D, Higgs DR.
An interspecies analysis reveals a key role for unmethylated CpG dinucleotides in vertebrate
Polycomb complex recruitment. (2011) EMBO J. 31(2):317-29
De Gobbi M, Garrick D, Lynch M, Vernimmen D, Hughes JR, Goardon N, Luc S, Lower KM,
Sloane-Stanley JA, Pina C, Soneji S, Renella R, Enver T, Taylor S, Jacobsen SE, Vyas P,
Gibbons RJ, Higgs DR. Generation of bivalent chromatin domains during cell fate decisions.
(2011) Epigenetics Chromatin. 4(1):9.
Law MJ and Lower KM, Voon HP, Hughes JR, Garrick D, Viprakasit V, Mitson M, De Gobbi
M, Marra M, Morris A, Abbott A, Wilder SP, Taylor S, Santos GM, Cross J, Ayyub H, Jones
S, Ragoussis J, Rhodes D, Dunham I, Higgs DR, Gibbons RJ. ATR-X syndrome protein
targets tandem repeats and influences allele-specific expression in a size-dependent
manner. (2010) Cell. 143(3):367-78.
Kassouf MT, Hughes JR, Taylor S, McGowan SJ, Soneji S, Green AL, Vyas P, Porcher C.
Genome-wide identification of TAL1's functional targets: insights into its mechanisms of
action in primary erythroid cells. Genome Res. (2010) 20(8):1064-83
Bee T, Liddiard K, Swiers G, Bickley SR, Vink CS, Jarratt A, Hughes JR, Medvinsky A, de
Bruijn MF. (2009) Alternative Runx1 promoter usage in mouse developmental
hematopoiesis. Blood Cells Mol Dis. (2009) 43(1):35-42.
Ballabio, E., Cantarella, CD., Federico, C., Di Mare, P., Hall, G., Harbott, J., Hughes, J.,
Saccone, S. and Tosi, S. (2009) Ectopic expression of the HLXB9 gene is associated with
an altered nuclear position in t(7;12) leukaemias, Leukemia 23 1179- 1182
Lower KM, Hughes JR, De Gobbi M, Henderson S, Viprakasit V, Fisher C, Goriely A, Ayyub
H, Sloane-Stanley J, Vernimmen D, Langford C, Garrick D, Gibbons RJ, Higgs DR.
Adventitious changes in long-range gene expression caused by polymorphic structural
variation and promoter competition. (2009) Proc Natl Acad Sci U S A. 106(51):21771-6
Ten Key Publications Throughout your Career
Jim R Hughes, Nigel Roberts, Simon McGowan, Deborah Hay, Eleni Giannoulatou, Magnus
Lynch, Marco De Gobbi, Stephen Taylor, Richard Gibbons, Douglas R Higgs. Analysis of
hundreds of cis-regulatory landscapes at high resolution in a single, high-throughput
experiment. . Nature Genetics 01/2014; • 35.21 Impact Factor
Ana C Marques, Jim Hughes, Bryony Graham, Monika S Kowalczyk, Doug R Higgs, Chris P
Ponting. Chromatin signatures at transcriptional start sites separate two equally populated
yet distinct classes of intergenic long noncoding RNAs. Genome biology (2013) 10.30
Impact Factor
Hughes JR and Kowalczyk MS, Garrick D and Lynch MD, Sharpe JA, Sloane-Stanley JA,
McGowan SJ, De Gobbi M, Hosseini M, Vernimmen D, Brown JM, Gray NE, Collavin L,
Gibbons RJ, Flint J, Taylor S, Buckle VJ, Milne TA, Wood WG, Higgs DR. Intragenic
enhancers act as alternative promoters. (2012) Mol Cell. 45(4):4 47-58
Law MJ and Lower KM, Voon HP, Hughes JR, Garrick D, Viprakasit V, Mitson M, De Gobbi
M, Marra M, Morris A, Abbott A, Wilder SP, Taylor S, Santos GM, Cross J, Ayyub H, Jones
S, Ragoussis J, Rhodes D, Dunham I, Higgs DR, Gibbons RJ. ATR-X syndrome protein
targets tandem repeats and influences allele-specific expression in a size-dependent
manner. (2010) Cell. 143(3):367-78.
Kassouf MT, Hughes JR, Taylor S, McGowan SJ, Soneji S, Green AL, Vyas P, Porcher C.
Genome-wide identification of TAL1's functional targets: insights into its mechanisms of
action in primary erythroid cells. Genome Res. (2010) 20(8):1064-83
Lower KM, Hughes JR, De Gobbi M, Henderson S, Viprakasit V, Fisher C, Goriely A, Ayyub
H, Sloane-Stanley J, Vernimmen D, Langford C, Garrick D, Gibbons RJ, Higgs DR.
Adventitious changes in long-range gene expression caused by polymorphic structural
variation and promoter competition. (2009) Proc Natl Acad Sci U S A. 106(51):21771-6
De Gobbi, M., Viprakasit, V., Hughes, J.R., Fisher, C., Buckle, V.J., Ayyub, H., Gibbons,
R.J., Vernimmen, D., Yoshinaga, Y., de Jong, P., Cheng, J.F., Rubin, E.M., Wood, W.G.,
Bowden, D. & Higgs, D.R. (2006) A regulatory SNP causes a human genetic disease by
creating a new transcriptional promoter. Science, 312, 1215-1217.
Hughes, J.R., Cheng, J.F., Ventress, N., Prabhakar, S., Clark, K., Anguita, E., De Gobbi, M.,
de Jong, P., Rubin, E. & Higgs, D.R. (2005) Annotation of cis-regulatory elements by
identification, subclassification, and functional assessment of multispecies conserved
sequences. Proc Natl Acad Sci U S A, 102, 9830-9835.
Hughes, J., Ward, C.J., Aspinwall, R., Butler, R. & Harris, P.C. (1999) Identification of a
human homologue of the sea urchin receptor for egg jelly: a polycystic kidney disease-like
protein. Hum Mol Genet, 8, 543-549.
Hughes, J., Ward, C.J., Peral, B., Aspinwall, R., Clark, K., San Millan, J.L., Gamble, V. &
Harris, P.C. (1995) The polycystic kidney disease 1 (PKD1) gene encodes a novel protein
with multiple cell recognition domains. Nat Genet, 10, 151-160.
Markers of Esteem
Appointed Associate Professor of Genome Biology (University of Oxford)
Current Grant Support
Core MRC Funding
MRC Centenary Award