The regulation of globin gene expression during haematopoiesis
Lead Research Organisation:
University of Oxford
Department Name: UNLISTED
Abstract
We now have an approximate map of the DNA sequence for the entire human genome. However the basic DNA sequence is only a starting block for understanding the complex interplay of factors which regulate the ability of a gene to make the correct protein at the correct time and in the correct cell type. We have a very detailed map of a region of chromosome 16. We want to characterise this region by identifying all the genes and regulatory features within the sequence, and then to look at additional (epigenetic) factors which can influence when and where a gene becomes active. DNA coils down within a cell nucleus with several proteins to form chromatin. We would like to understand how this chromatin is arranged within a nucleus and what changes may be necessary to allow genes to be switched on or off. Within this region of chromosome 16 lie the alpha globin genes. These genes make part of the molecule haemoglobin which carries oxygen in the blood and lack of haemoglobin will give rise to anaemia, which can cause malfunctions in the organs normally supplied with oxygen. When the alpha globin genes are disrupted in some way, patients develop a severe form of anaemia called alpha thalassaemia. Some patients are born with mental retardation and other developmental problems as well as alpha thalassaemia - these patients have a piece of chromosome 16 missing from the region we are studying. With the information from our mapping work and studies of nuclear organisation, we will identify precisely which genes are missing in these patients and how that loss contributes to their mental and developmental difficulties.
Technical Summary
Now that DNA sequence is available for many mammalian genomes, recent studies have focused on genome-wide approaches to determine how the key elements are organized; how this relates to nuclear function (including DNA replication, recombination and repair, DNA transcription and RNA processing), and how these processes are influenced by interactions with epigenetic phenomena (nuclear position, timing of replication, chromatin modifications and DNA modifications by methylation and hydroxymethylation). In future we plan to use such approaches to analyse how genes are regulated during haematopoiesis and particularly in erythropoiesis. Valuable as this ‘big picture’ is, it is critical that the generalities it produces are assessed for their accuracy by examination of individual loci whose detailed structure and many natural variants have been determined, and whose function can be verified by experimental manipulation. The ? globin locus and the surrounding region is one of the best characterised segments of the genome (in mouse and human) and therefore is ideal for testing predictions from the genome-wide studies. Equally, we will continue to test predictions made about nuclear processes from detailed analysis of this region by genome-wide studies. The ultimate goal of this work is to develop new ways to modify gene expression during erythropoiesis with the aim of manipulating globin gene expression and ameliorating the clinical phenotypes of patients with thalassaemia.
People |
ORCID iD |
Douglas Higgs (Principal Investigator) |
Publications
Babbs C
(2020)
ATR-16 syndrome: mechanisms linking monosomy to phenotype.
in Journal of medical genetics
Babbs C
(2020)
Variable cells with identical genetic codes.
in Blood
Badat M
(2017)
Gene Therapy in a Patient with Sickle Cell Disease.
in The New England journal of medicine
Blobel GA
(2021)
Testing the super-enhancer concept.
in Nature reviews. Genetics
Bozhilov YK
(2021)
A gain-of-function single nucleotide variant creates a new promoter which acts as an orientation-dependent enhancer-blocker.
in Nature communications
Brown JM
(2018)
A tissue-specific self-interacting chromatin domain forms independently of enhancer-promoter interactions.
in Nature communications
Chiariello AM
(2020)
A Dynamic Folded Hairpin Conformation Is Associated with a-Globin Activation in Erythroid Cells.
in Cell reports
Davies JO
(2017)
How best to identify chromosomal interactions: a comparison of approaches.
in Nature methods
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00016/1 | 31/03/2017 | 30/03/2022 | £3,035,000 | ||
MC_UU_00016/2 | Transfer | MC_UU_00016/1 | 31/03/2017 | 30/03/2022 | £3,411,000 |
MC_UU_00016/3 | Transfer | MC_UU_00016/2 | 31/03/2017 | 30/03/2022 | £1,366,000 |
MC_UU_00016/4 | Transfer | MC_UU_00016/3 | 31/03/2017 | 30/03/2020 | £3,017,000 |
MC_UU_00016/5 | Transfer | MC_UU_00016/4 | 31/03/2017 | 30/03/2020 | £497,000 |
MC_UU_00016/6 | Transfer | MC_UU_00016/5 | 31/03/2017 | 30/03/2022 | £2,530,000 |
MC_UU_00016/7 | Transfer | MC_UU_00016/6 | 31/03/2017 | 30/03/2022 | £2,018,000 |
MC_UU_00016/8 | Transfer | MC_UU_00016/7 | 31/03/2017 | 30/03/2018 | £1,131,000 |
MC_UU_00016/9 | Transfer | MC_UU_00016/8 | 31/03/2017 | 30/03/2022 | £2,500,000 |
MC_UU_00016/10 | Transfer | MC_UU_00016/9 | 31/03/2017 | 30/03/2018 | £1,171,000 |
MC_UU_00016/11 | Transfer | MC_UU_00016/10 | 31/03/2017 | 30/03/2022 | £1,387,000 |
MC_UU_00016/12 | Transfer | MC_UU_00016/11 | 31/03/2017 | 30/03/2022 | £446,000 |
Description | Anya Sturdy Charitable Trust for Medical Research |
Amount | £68,000 (GBP) |
Organisation | Anya Sturdy Charitable Trust for Medical Research |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2018 |
End | 04/2019 |
Description | BRC3 Haematology and Stem Cell |
Amount | £4,602,645 (GBP) |
Funding ID | BRC3 |
Organisation | National Institute for Health Research |
Department | NIHR Biomedical Research Centre |
Sector | Public |
Country | United Kingdom |
Start | 03/2017 |
End | 03/2022 |
Description | Capital Prioritisation for MRC Units and Institutes |
Amount | £75,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2018 |
End | 03/2019 |
Description | Capital Prioritisation for MRC Units and Institutes |
Amount | £300,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2018 |
End | 04/2019 |
Description | Establishing tools for dual RNA labelling in living cells to investigate how shared enhancers regulate expression of two genes |
Amount | £9,875 (GBP) |
Organisation | University of Oxford |
Department | Medical Sciences Division |
Sector | Academic/University |
Country | United Kingdom |
Start | 01/2019 |
End | 07/2019 |
Description | Establishment of a collaborative network of cllinicians and scientists workinh on novel genetic-based therapies for beta thalassaemia |
Amount | £24,500 (GBP) |
Organisation | Academy of Medical Sciences (AMS) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2018 |
End | 08/2019 |
Description | Exploring mechanisms of enhancer action in erythropoiesis |
Amount | £250,000 (GBP) |
Funding ID | 209181 |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2018 |
End | 03/2022 |
Description | Identifying suppressor mutations of ATR-X and ADNP syndromes using a novel CRISPR-based screening method in mice |
Amount | £250,000 (GBP) |
Funding ID | 210913 |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 11/2018 |
End | 10/2022 |
Description | The Role of Megakaryocytes in Myeloproliferative Neoplasms. |
Amount | £309,426 (GBP) |
Funding ID | 107477/Z/15/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 07/2016 |
End | 08/2019 |
Description | WIMM - MRC Festival Establishment Award |
Amount | £3,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 02/2019 |
End | 03/2024 |
Description | WIMM - WIMM MHU Capital Funding Award 2019/20 |
Amount | £85,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2019 |
End | 03/2020 |
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Organisation | University of Oxford |
Department | Wellcome Trust Centre for Human Genetics |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | We have provided DHS analysis and made all RNA from 10 strains of mice for deep sequence analysis at the Sanger Centre |
Collaborator Contribution | Analysis and interpretation |
Impact | none |
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Organisation | University of Oxford |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Access to ovarian cancer biology and computational work |
Collaborator Contribution | Immunology expertise and cancer antigene prediction. |
Impact | The Ovarian Cancer Action (OCA) international grand challenge award Publication by Cancer Cell in Feb 2020: " The Repertoire of Serous Ovarian Cancer Non-genetic Heterogeneity Revealed by Single-Cell Sequencing of Normal Fallopian Tube Epithelial Cells" |
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Organisation | University of Oxford |
Department | Wellcome Trust Centre for Human Genetics |
Country | United Kingdom |
Sector | Charity/Non Profit |
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Collaborator Contribution | Sequencing and interpretation |
Impact | Manuscript submitted to Nature Genetics |
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Description | The role of boundary elements |
Organisation | National Institutes of Health (NIH) |
Country | United States |
Sector | Public |
PI Contribution | Research Input |
Collaborator Contribution | Interpretation |
Impact | None yet |
Start Year | 2010 |
Description | 11th Cooley's Anemia Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists. |
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Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
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Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists. |
Year(s) Of Engagement Activity | 2021 |
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Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
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Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists. |
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Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists. |
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Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists. |
Year(s) Of Engagement Activity | 2021 |
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Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists. |
Year(s) Of Engagement Activity | 2021 |
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Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists. |
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Form Of Engagement Activity | A talk or presentation |
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Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists. |
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Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Undergraduate students |
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Year(s) Of Engagement Activity | 2013,2014,2015,2016,2017,2018,2019 |
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Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists. |
Year(s) Of Engagement Activity | 2023 |
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Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | A talk regarding the work on single-cell systems biology carried out by the company to date. This sparked a good debate between the presenter and the audience. |
Year(s) Of Engagement Activity | 2016,2017,2018,2019 |
Description | Oxford TEE meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists. |
Year(s) Of Engagement Activity | 2022 |
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Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | The presentation was part of the Royal Society Summer Exhibition attended by schoolchildren, members of the public and members of the scientific community. This exhibition is probably the largest of the year in terms of attendees over the course of a week. |
Year(s) Of Engagement Activity | 2017 |
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Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Postgraduate students |
Results and Impact | A career talk to students and post-docs involving working in the USA |
Year(s) Of Engagement Activity | 2016 |
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Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists. |
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Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
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Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists. |
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Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists. |
Year(s) Of Engagement Activity | 2022 |