The role of spatial nuclear organisation in genome function
Lead Research Organisation:
University of Edinburgh
Department Name: UNLISTED
Abstract
The linear sequence map of the DNA that makes up our human genome is an incomplete description of our genetic information. This is because information on genome function and gene regulation is also encoded in the way that the DNA sequence is folded up with proteins within chromosomes and within the cell nucleus. Our work tries to understand the three-dimensional folding of the genome, and how this controls how our genome functions in normal development and how this may be perturbed in disease. A particularly important question is how genes are controlled in time and space by elements in our genome called enhancers that can located far away from the genes that they control. This is an important area of human genetics because most of the common genetic variation between individuals in a population that affects our life-time risk of developing disease, lies in enhancers. A prominent feature of our work is the use of visual assays to investigate how the genome is folded up. To do this we combine fluorescence in situ hybridisation (FISH) and digital microscopy with the use of automated image analysis software.
Technical Summary
The regulation of gene expression is controlled by enhancers that are often located at very large genomic distance from their target genes. Mutation of enhancers underlies many cases of severe human developmental disorders and common sequence variation at enhancers contributes to a large proportion of complex genetic disease and quantitative traits. Functional interpretation of the DNA sequence variation revealed by large-scale whole human genome sequencing efforts requires a much better understanding of how enhancers work and is a major challenge in human genomics.
We will probe mechanisms of chromosome folding linked to enhancer function and to spatial positioning in the nucleus. To gain mechanistic insight into the molecular events required to activate a gene from a distance, we will use multi-disciplinary approaches – from high-throughput chromatin profiling to advanced optical imaging - integrated with synthetic biology tools that allow us to dissect cause/consequence relationships between chromatin organisation and genome function. We will test models of enhancer-promoter communication and will determine what factors are required to bind at enhancers in order to instigate the different steps of transcription. We will focus on exemplar loci that are paradigms for long-range cis-regulation (e.g. Shh and Pax6) but, with collaborators, will also help drive the functional follow-up of loci identified by genome-wide association studies (GWAS) and that involve common genetic variation at enhancers.
We will probe mechanisms of chromosome folding linked to enhancer function and to spatial positioning in the nucleus. To gain mechanistic insight into the molecular events required to activate a gene from a distance, we will use multi-disciplinary approaches – from high-throughput chromatin profiling to advanced optical imaging - integrated with synthetic biology tools that allow us to dissect cause/consequence relationships between chromatin organisation and genome function. We will test models of enhancer-promoter communication and will determine what factors are required to bind at enhancers in order to instigate the different steps of transcription. We will focus on exemplar loci that are paradigms for long-range cis-regulation (e.g. Shh and Pax6) but, with collaborators, will also help drive the functional follow-up of loci identified by genome-wide association studies (GWAS) and that involve common genetic variation at enhancers.
People |
ORCID iD |
Wendy Bickmore (Principal Investigator) |
Publications
Athmane N
(2021)
MUC4 is not expressed in cell lines used for live cell imaging
in Wellcome Open Research
Athmane N
(2021)
MUC4 is not expressed in cell lines used for live cell imaging.
in Wellcome open research
Benabdallah NS
(2019)
Decreased Enhancer-Promoter Proximity Accompanying Enhancer Activation.
in Molecular cell
Bhatia S
(2021)
Quantitative spatial and temporal assessment of regulatory element activity in zebrafish.
in eLife
Bickmore WA
(2019)
Patterns in the genome.
in Heredity
Boumendil C
(2019)
Nuclear pore density controls heterochromatin reorganization during senescence.
in Genes & development
Boumendilrid C
(2018)
Nuclear pore density controls heterochromatin reorganization during senescence
Boyle S
(2020)
A central role for canonical PRC1 in shaping the 3D nuclear landscape.
in Genes & development
Bruneau BG
(2019)
Chromatin and epigenetics in development: a Special Issue.
in Development (Cambridge, England)
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00007/1 | 01/04/2018 | 31/03/2023 | £662,000 | ||
MC_UU_00007/2 | Transfer | MC_UU_00007/1 | 01/04/2018 | 31/03/2023 | £3,730,000 |
MC_UU_00007/3 | Transfer | MC_UU_00007/2 | 01/04/2018 | 31/05/2022 | £3,053,000 |
MC_UU_00007/4 | Transfer | MC_UU_00007/3 | 01/04/2018 | 31/03/2023 | £1,772,000 |
MC_UU_00007/5 | Transfer | MC_UU_00007/4 | 01/04/2018 | 31/03/2023 | £4,524,000 |
MC_UU_00007/6 | Transfer | MC_UU_00007/5 | 01/04/2018 | 31/03/2023 | £2,878,000 |
MC_UU_00007/7 | Transfer | MC_UU_00007/6 | 01/04/2018 | 31/03/2023 | £2,829,000 |
MC_UU_00007/8 | Transfer | MC_UU_00007/7 | 01/04/2018 | 31/12/2022 | £4,072,000 |
MC_UU_00007/9 | Transfer | MC_UU_00007/8 | 01/04/2018 | 31/03/2023 | £3,137,000 |
MC_UU_00007/10 | Transfer | MC_UU_00007/9 | 01/04/2018 | 31/03/2023 | £6,948,000 |
MC_UU_00007/11 | Transfer | MC_UU_00007/10 | 01/04/2018 | 31/03/2023 | £2,421,000 |
MC_UU_00007/12 | Transfer | MC_UU_00007/11 | 01/04/2018 | 31/03/2023 | £1,205,000 |
MC_UU_00007/13 | Transfer | MC_UU_00007/12 | 01/04/2018 | 31/03/2023 | £1,174,000 |
MC_UU_00007/14 | Transfer | MC_UU_00007/13 | 01/04/2018 | 31/03/2023 | £1,838,000 |
MC_UU_00007/15 | Transfer | MC_UU_00007/14 | 01/04/2018 | 31/03/2023 | £2,551,000 |
MC_UU_00007/16 | Transfer | MC_UU_00007/15 | 01/04/2018 | 31/03/2023 | £1,496,000 |
MC_UU_00007/17 | Transfer | MC_UU_00007/16 | 01/04/2018 | 31/03/2023 | £1,886,000 |
Description | Scientific Advisory Board Sanger Institute |
Geographic Reach | National |
Policy Influence Type | Membership of a guideline committee |
Description | Understanding the role of nuclear pores in 3D genome organisation and function |
Amount | £509,382 (GBP) |
Funding ID | 217120/Z/19/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2019 |
End | 08/2024 |
Title | QSTARZ enhancer reporter assay cassette |
Description | We developed Q-STARZ (Quantitative Spatial and Temporal Assessment of Regulatory element activity in Zebrafish), a new and significantly improved design of a previous transgenic reporter assay, based upon targeted integration of a dual-CRE dual-reporter cassette into a pre-defined site in the zebrafish genome. A unique feature of this design is the single transgenic cassette containing both wild-type and mutant CREs, separated by strong insulator sequences, with the transcriptional potential of both CREs read out as expression of different fluorescent proteins. Qualitative and quantitative activity of the two CRE alleles is analyzed from eGFP/mCherry fluorescence in real-time by live imaging of embryos obtained from the founder (F0) lines bearing the dual CRE dual-reporter cassette. This allows robust, unbiased assessment of spatial and temporal activities of both CREs using a single transgenic line, thereby reducing animal usage by up to 75% compared to the previous design. We utilize disease-associated mutations in well characterized CREs from the PAX6 and SHH loci to demonstrate the salient features of the Q-STARZ method. |
Type Of Material | Technology assay or reagent |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | Too early to tell, but we have already received requests for the constructs for this assay from other researchers. We intend to deposit the relevant constructs in Addgene |
Title | NPD |
Description | Expertly curated database for mammalian nuclear proteins |
Type Of Material | Database/Collection of data |
Year Produced | 2010 |
Provided To Others? | Yes |
Impact | Not known |
URL | http://npd.hgu.mrc.ac.uk/user/about |
Description | Synthetic variation at the PAX6 locus |
Organisation | NYU Langone Medical Center |
Country | United States |
Sector | Academic/University |
PI Contribution | Functional testing of engineered PAX6 loci in vertebrate cell and organism systems |
Collaborator Contribution | Joint NSF/BBSRC grant. NYU collaborator is providing the expertise in synthetic biology using S.cerevisiae |
Impact | Too early for outputs |
Start Year | 2020 |
Description | Up-scaling human insulin-producing beta cell production by efficient differentiation and expansion of pancreatic endoderm progenitors |
Organisation | University of Copenhagen |
Department | Danish Stem Cell Center (DanStem) |
Country | Denmark |
Sector | Academic/University |
PI Contribution | Investigation of chromatin structure changes during the early stages of endoderm differentiation |
Collaborator Contribution | Development and provision of reporter embryonic stem cell lines and differentiation protocols |
Impact | Development of the Hum-en website and diabetes information for the public |
Start Year | 2014 |
Title | Coolpup.py |
Description | Algorithm for efficient pile-up of Hi-C data |
Type Of Technology | Webtool/Application |
Year Produced | 2020 |
Open Source License? | Yes |
Impact | Widely used and being cited in publications |
Description | Discovery Zone, Chelsea Flower Show |
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 | Exhibit at the Chelsea flower show to celebrate the centenary of the Genetics Society. The genetics of flower colour and form |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.ed.ac.uk/mrc-human-genetics-unit/news-and-events/latest-news/genetics-garden-wins-silver... |
Description | MRC Festival of Science |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | "Shining a light on Genetic Disorders". Dialogue between researchers and patients. |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.ed.ac.uk/mrc-human-genetics-unit/news-and-events/latest-news/shining-a-light-on-genetics... |
Description | Podcast |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Podcast for the Lonely Pipettes - about career path and research culture |
Year(s) Of Engagement Activity | 2021 |
URL | https://podcasts.apple.com/gb/podcast/tlp-7-its-okay-to-be-wrong-wendy-bickmore/id1532120809?i=10005... |
Description | Press release and press coverage |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Press release on our work on senescence was widely picked up by the national and international press. https://www.edinburghnews.scotsman.com/news/health/edinburgh-university-study-sheds-light-on-how-to-stop-damaging-effects-of-ageing-1-4873531 (includes a quote from CRUK) https://www.irishexaminer.com/breakingnews/world/damaging-effects-of-ageing-could-be-prevented-scientists-claim-904424.html https://www.independent.ie/life/health-wellbeing/damaging-effects-of-ageing-could-be-prevented-new-research-37816323.html https://nypost.com/2019/02/14/miracle-anti-aging-pill-nearer-reality-after-breakthrough/ https://www.breakingnews.ie/world/damaging-effects-of-ageing-could-be-prevented-scientists-claim-904424.html https://www.news-medical.net/news/20190215/Cell-manipulation-could-soon-halt-or-reverse-aging.aspx https://www.sciencedaily.com/releases/2019/02/190214100036.htm |
Year(s) Of Engagement Activity | 2019 |
Description | Public talk on the future of Human Genetics |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Field, farm and family debate associated with the 100 years of Genetics conference. |
Year(s) Of Engagement Activity | 2019 |
Description | Radio interview |
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 | Interview about our work on senescence on Radio 4's Today programme. |
Year(s) Of Engagement Activity | 2019 |
Description | Radio interview (BBC Scotland) |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Radio interview on Good Morning Scotland (BBC Scotland) about our work on senescence |
Year(s) Of Engagement Activity | 2019 |
Description | Radio interview (World Service) |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Radio interview on the World Service about our work on senescence |
Year(s) Of Engagement Activity | 2019 |
Description | Visit from Scottish Government Cabinet Secretary flor Health |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | Visit to the Genomic Data Analysis Centre providing genome interpretation for rare disease for NHS Scotland. |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.ed.ac.uk/mrc-human-genetics-unit/news-and-events/latest-news/jeane-freeman-msp-mrc-visit |