Functional genomics and development of clinical genome editing strategies
Lead Research Organisation:
University of Oxford
Department Name: UNLISTED
Abstract
The Davies laboratory aims to understand how the genome is read by the cells of the blood and bone marrow
and how the sequence can be edited to treat human disease. This is important because genetic variation in bloodcells alters the susceptibility to many different human diseases including infection, autoimmune disease and
malignancy. Genome editing of these cells has the potential to cure many diseases but this technology can only be safely used if we understand the effects of altering the genome sequence.
Over 90% of all DNA sequences that are associated with human disease alter how genes are controlled rather
than in the protein produced by the gene. The laboratory has world class expertise in developing new techniques
for determining the physical structure of DNA within cells, which is key to understanding how the genome
functions. We will use this technology to investigate the fundamental principles that control genes. We will also
use it to map the key DNA sequences that control genes in important blood and bone marrow cell types.
We aim to translate this by developing new and safer ways of editing the genome of bone marrow stem cells
which can be transplanted to treat human disease.
and how the sequence can be edited to treat human disease. This is important because genetic variation in bloodcells alters the susceptibility to many different human diseases including infection, autoimmune disease and
malignancy. Genome editing of these cells has the potential to cure many diseases but this technology can only be safely used if we understand the effects of altering the genome sequence.
Over 90% of all DNA sequences that are associated with human disease alter how genes are controlled rather
than in the protein produced by the gene. The laboratory has world class expertise in developing new techniques
for determining the physical structure of DNA within cells, which is key to understanding how the genome
functions. We will use this technology to investigate the fundamental principles that control genes. We will also
use it to map the key DNA sequences that control genes in important blood and bone marrow cell types.
We aim to translate this by developing new and safer ways of editing the genome of bone marrow stem cells
which can be transplanted to treat human disease.
Technical Summary
The Davies laboratory focuses on understanding gene regulation through combining genomics, bioinformatics and genome editing approaches. We also have a major interest in translating this expertise to develop clinical genome editing strategies for treating human disease in the context of haemopoietic stem cell transplantation.
Many genes are controlled by regulatory elements called promoters that lie adjacent to the transcription start site and enhancers that are located 104-106 base pairs distant from the gene. The laboratory have developed an innovative technique called Micro Capture-C (MCC), which makes it possible to define physical contacts at base pair resolution when previous methods have limited resolution below 500 base pairs. We will explore the fundamental mechanisms controlling gene regulation by improving this approach and combining it with other functional genomics approaches. This will include the use of degrons to remove key components of the transcriptional machinery. Through extensive collaboration within the MHU we wish to map the chromatin landscape to understand how variants in enhancers cause abnormal haemopoiesis. We will also engineer cellular models to test the function of perturbing regulatory elements at scale including the use of CRISPR screens.
Having previously developed clinical approaches for treating haemoglobinopathies using base editing; we plan to go on to develop a method of editing haemopoietic stem cells to improve the safety of transplantation through inducing a druggable selective advantage. In addition, we are using our expertise in functional genomics to assess the safety of genome editing approaches, in which the majority of off-target mutations occur in the non-coding genome.
Many genes are controlled by regulatory elements called promoters that lie adjacent to the transcription start site and enhancers that are located 104-106 base pairs distant from the gene. The laboratory have developed an innovative technique called Micro Capture-C (MCC), which makes it possible to define physical contacts at base pair resolution when previous methods have limited resolution below 500 base pairs. We will explore the fundamental mechanisms controlling gene regulation by improving this approach and combining it with other functional genomics approaches. This will include the use of degrons to remove key components of the transcriptional machinery. Through extensive collaboration within the MHU we wish to map the chromatin landscape to understand how variants in enhancers cause abnormal haemopoiesis. We will also engineer cellular models to test the function of perturbing regulatory elements at scale including the use of CRISPR screens.
Having previously developed clinical approaches for treating haemoglobinopathies using base editing; we plan to go on to develop a method of editing haemopoietic stem cells to improve the safety of transplantation through inducing a druggable selective advantage. In addition, we are using our expertise in functional genomics to assess the safety of genome editing approaches, in which the majority of off-target mutations occur in the non-coding genome.
Publications
Aljahani A
(2022)
Analysis of sub-kilobase chromatin topology reveals nano-scale regulatory interactions with variable dependence on cohesin and CTCF.
in Nature communications
Badat M
(2023)
Direct correction of haemoglobin E ß-thalassaemia using base editors.
in Nature communications
Crump N
(2023)
MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia
in Nature Communications
Downes DJ
(2023)
Author Correction: Capture-C: a modular and flexible approach for high-resolution chromosome conformation capture.
in Nature protocols
Downes DJ
(2022)
Capture-C: a modular and flexible approach for high-resolution chromosome conformation capture.
in Nature protocols
Hamley JC
(2023)
Determining chromatin architecture with Micro Capture-C.
in Nature protocols
Maresca M
(2023)
Pioneer activity distinguishes activating from non-activating SOX2 binding sites.
in The EMBO journal
Preston AE
(2023)
Ancient genomic linkage couples metabolism with erythroid development.
in bioRxiv : the preprint server for biology
Robbe P
(2022)
Whole-genome sequencing of chronic lymphocytic leukemia identifies subgroups with distinct biological and clinical features.
in Nature genetics
Turkalj S
(2023)
GTAC enables parallel genotyping of multiple genomic loci with chromatin accessibility profiling in single cells
in Cell Stem Cell
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00029/1 | 01/04/2022 | 31/03/2027 | £4,671,000 | ||
MC_UU_00029/2 | Transfer | MC_UU_00029/1 | 01/04/2022 | 31/03/2027 | £2,140,000 |
MC_UU_00029/3 | Transfer | MC_UU_00029/2 | 01/04/2022 | 31/03/2027 | £3,857,000 |
MC_UU_00029/4 | Transfer | MC_UU_00029/3 | 01/04/2022 | 31/03/2027 | £1,339,000 |
MC_UU_00029/5 | Transfer | MC_UU_00029/4 | 01/04/2022 | 31/03/2027 | £2,875,000 |
MC_UU_00029/6 | Transfer | MC_UU_00029/5 | 01/04/2022 | 31/03/2027 | £1,968,000 |
MC_UU_00029/7 | Transfer | MC_UU_00029/6 | 01/04/2022 | 31/03/2027 | £1,450,000 |
MC_UU_00029/8 | Transfer | MC_UU_00029/7 | 01/04/2022 | 31/03/2027 | £2,507,000 |
MC_UU_00029/9 | Transfer | MC_UU_00029/8 | 01/04/2022 | 31/03/2027 | £3,688,000 |
Description | Blood and Transplant Research Unit in Precision Cellular Therapeutics |
Amount | £4,000,412 (GBP) |
Funding ID | NIHR203339 |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 04/2022 |
End | 04/2027 |
Description | Decoding human non-coding disease genetics en masse using Micro Capture-C and Deep Neural Network Machine learning |
Amount | £3,738,985 (GBP) |
Funding ID | 225220/Z/22/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2022 |
End | 09/2027 |
Description | Lister Research Prize Fellowship |
Amount | £250,000 (GBP) |
Organisation | Lister Institute of Preventive Medicine |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 10/2022 |
End | 10/2027 |
Description | Collaboration to use machine learning and Micro Capture-C to decode non-coding genetics |
Organisation | University of Oxford |
Department | Big Data Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Collaboration between my group and Prof J Hughes at the MRC WIMM and the BDI ( Prof Cecelia Lindgren) to use machine learning to decode non-coding human genetics |
Collaborator Contribution | Technical support on the machine learning aspects of the project |
Impact | The collaboration has resulted in a Discovery Award from Wellcome |
Start Year | 2022 |
Description | Collaboration to use machine learning and Micro Capture-C to identify regulatory elements in HIV |
Organisation | University Libre Bruxelles (Université Libre de Bruxelles ULB) |
Country | Belgium |
Sector | Academic/University |
PI Contribution | Our team has assisted with experimental work and advice. |
Collaborator Contribution | Provided cellular models |
Impact | Data generation in progress |
Start Year | 2022 |
Company Name | NUCLEOME THERAPEUTICS LIMITED |
Description | Nucleome Limited is a spinout from the University of Oxford with patented technology that defines the 3D structure of the genome allowing us to link disease causing genetic variants located in the non-coding DNA to affected genes. This, together with our computational pipelines, powered by machine learning capabilities, and extensive molecular biology and genetic engineering expertise, forms a platform technology for novel therapeutic target discovery and development. |
Year Established | 2019 |
Impact | The company is an early stage startup. It has secured £5.2 million in seed funding from Oxford Sciences Innovation. The company has considerable interest from several large pharmaceutical companies including GSK and MERK. |
Website | http://www.nucleome.com |
Description | Articles in National Press including Times and Telegraph |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Article in the Times and Telegraph News papers about research. |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.thetimes.co.uk/article/the-date-with-a-neanderthal-that-led-to-a-million-covid-deaths-3h... |
Description | Cheltenham Science Festival |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | I was the main speaker at an event at the Cheltenham Science Festival. This was reported in the national media and had widespread engagement including a Youtube video, which has had over 600,000 views. |
Year(s) Of Engagement Activity | 2022 |
URL | https://issuu.com/cheltenhamfestivals/docs/csf_2022_brochure_final |
Description | ITV news interview |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Interview for ITV meridian news about the structure of DNA |
Year(s) Of Engagement Activity | 2023 |
Description | PPIE engagement for NIHR Blood and Transplant Research Unit |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Engagement with PPIE group about the direction of the research programme |
Year(s) Of Engagement Activity | 2022 |