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  • Jim Hughes

ABOUT THE RESEARCH

The Hughes group is interested in the basic mechanisms which control the activities of genes and how sequence changes in the regulatory non-coding portion of the genome alter gene expression and underlie common human diseases.  The sequences which codes for protein only represents ~2% of the human genome and this small fraction has been the focus of the majority of scientific scrutiny over the last 30 years.  However, work over the last decade and a half has shown that the vast majority of sequence changes that underlie most common human diseases, such as diabetes, cardiac, cancer, neurological and autoimmune diseases, lie in the non-coding rather than coding portion of the genome. The development of complex multicellular organisms is completely dependent on the exquisitely orchestrated expression of gene networks, as is our cells’ abilities to react to stimuli from our environment. It is therefore suspected and, in some cases, confirmed, that these changes in our non-coding genome alter the behaviour of embedded regulatory elements and so effect the “how” and “where” such genes are expressed, rather than the structure of the proteins themselves.

To understand the link between our genomes and our susceptibility to common diseases it is therefore imperative to understand both the mechanisms by which genes are normally regulated and how such sequence variation can alter the output of such regulatory circuits.  The interrogation of the non-coding genome and gene regulation are demanding questions and requires the application and development of cutting edge computational and molecular approaches.  The Hughes group in expert in both molecular and computational approaches developing novel molecular assays, such as Capture-C and Micro Capture-C and novel computational machine learning approaches such as DeepC.  It is also expert in the use and analysis of a wide range of genomics methods (ATAC-seq, ChIP-seq, transcriptomics and Chromatin Conformation Capture (3C) methods) and is also leveraging them at the single cell level to map out regulatory landscapes in the non-coding genomes of complex cellular systems.

Some current projects cover the basic biology of gene regulation as well as genomics and synthetic biology method development.  Other projects investigate the role of non-coding sequence variation in human disease predisposition or progression.  Projects are highly collaborative, linking groups, both locally and internationally with domain expertise in human diseases, genome biology and synthetic biology. 

Additional supervision will be provided by Professor Tom Milne, Professor James Davies and Professor Adam Mead.

Please see the Weatherall Institute for Molecular Medicine (WIMM) for information about applications for a DPhil in Medical Sciences with groups based in the WIMM.

 

TRAINING OPPORTUNITIES

DPhil opportunities exist for both purely computational research and for bench research.  The computational projects would suit a candidate with a strong computer science, mathematical or statistical background and will focus on using Deep Neural Network approaches to model regulatory function in the human genome. No formal biological background is required, and the candidate will be trained in the analysis and interpretation of genomics and epigenomics data.  The bench projects would suit a candidate with a biological background and the student will learn how to perform genomics methods such as ATAC-seq, ChIP-seq and RNA-seq, as well as specialist 3D genome 3C methods such as Capture-C, Tiled-C and Hi-C.   The group focuses on leveraging new single cell epigenetic (scATAC-seq) and multimodal technologies (scATAC-seq combined with scRNA-seq), combining these with Deep Neural network analysis.

Students will be enrolled on the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies. 

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence, and impact. Students are actively encouraged to take advantage of the training opportunities available to them. 

As well as the specific training detailed above, students will have access to a wide range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

 

PUBLICATIONS

1

Hua, P et al (2021). Defining genome architecture at base-pair resolution. Nature595: 125-129.

2

Larke et al (2021). Enhancers predominantly regulate gene expression during differentiation via transcription initiation. Mol Cell81: 983-997 e7.

3

Schwessinger, R et al.  (2020). DeepC: predicting 3D genome folding using megabase-scale transfer learning. Nat Methods17: 1118-1124.

4

Downes, D.J.et al (2021). High-resolution targeted 3C interrogation of cis-regulatory element organization at genome-wide scale. Nat Commun12: 531.

5

Oudelaar, A.M. et al (2020). Dynamics of the 4D genome during in vivo lineage specification and differentiation. Nat Commun11: 2722.

6

Oudelaar, A.M. et al (2018). Single-allele chromatin interactions identify regulatory hubs in dynamic compartmentalized domains. Nat Genet 50, pages1744–1751