Gene Control Mechanisms and Disease

Lead Research Organisation: MRC London Institute of Medical Sciences

Abstract

Although nearly every cell contains two copies of every gene, different types of cells have distinct features. As we are made from billions of cells how is the genetic information controlled? Clearly, not all genes are active in all cells. Our research focuses on how different cells know to switch on some genes but not others. It is now clear that this involves packaging the genes in different ways in the nucleus. Between the genes themselves, which are made of DNA, are non-coding DNA sequences that control whether the gene is on or off in a particular cell. We have shown that some sequences can open the DNA allowing the nearby gene to switch on whereas other sequences have the opposite effect and close the DNA into a densely packaged compartment. There are many proteins that package the DNA, we have shown that we can affect the probability of switching genes on or off by including repetitive DNA close by to the gene or by changing the amount of packaging proteins available. We think that this is what happens in some neurological diseases. Using transgenic mice we have shown that we could reverse this abnormal silencing. This finding opens up new possibilities for treating as yet incurable diseases. We are presently focusing on several examples, including the neurodegenerative disease Friedreichs ataxia, and have shown that we can reverse abnormal silencing in cells from patients with this disease. Such an approach could lead to a treatment. Our work will also shed light on how males apparently can switch some genes off more easily than females. Such information is important for understanding why some diseases might affect the sexes differently. Our research is on the fundamentals of how cells regulate genes during development and is therefore likely to reveal crucial information as to how stem cells can replace a variety of different cell types and stably maintain the correct gene regulation in these cells.

Technical Summary

Our research is aimed at unravelling the molecular mechanisms underlying epigenetic memory in mammals whereby cells establish and maintain gene expression patterns, and at understanding how dysregulation at this level leads to human diseases. Such research is crucial for the development of novel treatments for several diseases by modulating chromatin structure and for the development of reliable gene therapy protocols as well as understanding the plasticity of stem cells. The research builds on our finding that a gene-regulatory element known as a locus control region (LCR) can overcome gene silencing mediated by proximity to highly repetitive heterochromatic genomic regions. We have shown that in the absence of the LCR such silencing strongly resembles the archetypal epigenetic phenomenon of position effect variegation (PEV), hitherto demonstrated in Drosophila and yeast. By studying modifiers of PEV in an in vivo mammalian system we have shown that aberrant silencing associated with several triplet-repeat diseases occurs at the level of heterochromatin and can be reversed in vivo; such silencing can not only be reversed by an LCR but can also be overcome by drugs known to modify chromatin structure. Recently we have uncovered important differences in the extent of heterochromatin silencing in male and female mice which is not determined by the gender of the mice but rather the number of X chromosomes - this finding has implications for understanding sexual dimorphism, a feature of many diseases, which is usually attributed to the male or female phenotypes. Our work currently focuses on the interplay between nuclear organisation, chromatin structure and epigenetic modifiers in establishing and maintaining the differentiated state of the cell. Our recent finding that a key component of the densely packaged form of DNA known as heterochromatin is in a continuous state of flux has shattered the previously held view that heterochromatin acted as a molecular glue. Our finding opens up the possibility of re-programming the genome even in so-called inaccessible heterochromatin regions. We are currently investigating the reversibility of such silencing in the neurological disease Friedreichs ataxia; this promises to provide a radical approach for treating this currently incurable condition.

Publications

10 25 50
 
Description A randomized double-blind placebo-controlled parallel-group multi-centre study of the efficacy and safety of nicotinamide in patients with Friedreich's ataxia (NICOFA)
Amount € 1,700,000 (EUR)
Organisation E-Rare 
Sector Public
Country France
Start 10/2017 
End 10/2020
 
Description BRC Imperial
Amount £140,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Imperial Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 07/2013 
End 12/2014
 
Description Efficacy and Mechanism Evaluation Programme NIHR/MRC EME Project:The UK arm of a multi-centre study of the efficacy and safety of nicotinamide in patients with Friedreich's ataxia (NICOFA)
Amount £900,000 (GBP)
Funding ID EME Project:17/90/01 
Organisation NIHR Evaluation, Trials and Studies Coordinating Centre (NETSCC) 
Sector Academic/University
Country United Kingdom
Start 03/2019 
End 10/2022
 
Description MRC Developmental Pathway Funding Scheme (DPFS)
Amount £351,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2009 
End 10/2012
 
Description Response mode project grant
Amount £863,446 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2012 
End 09/2016
 
Description Rutherford Innovation Fellowship
Amount £250,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 11/2017 
End 11/2019
 
Description Translational Project Grant Freidreich's ataxia
Amount £118,000 (GBP)
Organisation Ataxia UK 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2011 
End 12/2013
 
Title CTG -transgenics 
Description Inserted the triplet-repeat expansion associated with the commonest adult onset muscular dystrophy (Myotonic Dystrophy) into the cognate mouse locus to model the gene expression defect. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Established improved tractable model for studying gene expression perturbations in triplet-repeat diseases in vivo. 
 
Title FRDA cohort 
Description Set-up database for patients suffering from Friedreich's ataxia 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact Obtained PBLs, chromatin and RNA inorder to perform epigenotype/phenotype correlations. 
 
Title HP1beta-bio 
Description Established a murine model to enable chromatin immunoprecipitation and purification of protein complexes using a biotin-tagged version of heterochromatin-protein 1 expressed in vivo. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Will enable epigenomic maps to be established for this protein using ex vivo tissue circumventing technical problems the field has faced related to use of antibodies for this purpose. 
 
Title HP1gamma transgenics 
Description Murine model to explore function of key chromatin component. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Established that this modifier is a potential modifier of heterochromatin-mediated silencing and triplet-repeat diseases. 
 
Title Identification of histone H3 K4acetylation as a novel post-translational modification using a novel antibody 
Description Polyclonal antibody specific to histone H3 lysine 4 acetylation 
Type Of Material Technology assay or reagent 
Year Produced 2011 
Provided To Others? Yes  
Impact Identification that histone H3 is modified on a key residue, lysine 4, in yeast and mammals. This changes our understanding of how gene's are regulated in eukaryotes as indicated by our genome-wide epigenomic and functional studies. 
 
Title TROY 
Description Epigenome bioinformatics tool to visualise gene expression profiles simulataneously with genome-wide data provided by chromatin immunoprecipitation. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Has allowed rapid identification an interrogation of regions of the genome responding to epigenetic modifiers 
 
Title Motion Capture Suit analytics 
Description Developing methodology to analyse behaviourmetric data in Friedreich's ataxia 
Type Of Material Data analysis technique 
Provided To Others? No  
Impact The main impact promises to shorten the length of clinical trials by providing a more robust biomarker for disease progression by measuring movements during everyday living. 
 
Description AP 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom 
Sector Academic/University 
PI Contribution We extensively analysed the epigenetic marks and proteins bound to the Frataxin locus in Friedreich's ataxia and indentified abnormal bhaviour of RNAPolII at the locus
Collaborator Contribution Provided expertise in RNAPolII function
Impact This work identified a novel mode of gene regulation which is perturbed in Friedreich's ataxia and indentified a novel therapeutic target.
Start Year 2008
 
Description FC 
Organisation Institute of Genetics and Molecular and Cellular Biology (IGBMC)
Country France 
Sector Academic/University 
PI Contribution We analysed the effect of disrupting the interaction between a factor which targets heterochromatin-mediated silencing to genes in vivo.
Collaborator Contribution Provision of murine reagents enabling the conditional deletion and mutation of a co-activator molecule
Impact We found that the coactivator regulates the mobility of its interacting partner and modulates the stability of heterochromatin and the stability of gene silencing. Manuscript in preparation
Start Year 2006
 
Description Findacure 
Organisation Findacure
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Investigation with Findacure to calculate the cost benefits of reversing pathology in Friedreich's ataxia in order to make the case for funding a clinical trial of a novel disease modifying strategy in this disease
Collaborator Contribution Our collaborators provided methodology to model the economics of costs for looking after patients with Friedreich's ataxia
Impact This is a mutli-disciplinary projkect pulling together economics and health researchers
Start Year 2016
 
Description JG 
Organisation Imperial College London
Department MRC London Institute of Medical Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We have discovered potential sex-dimorphism in the regulation of cellular proliferation which is regulated by a heterochromatin component. The collaboration is allowing us to determine whether these gene expression changes result in an altered pronesity to senescence.
Collaborator Contribution JG has all the necessary prtocols set up to examine the senscent phenotype in detail and is haring expertise
Impact These studies are in progress.
Start Year 2016
 
Description JT 
Organisation Francis Crick Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Collaboration with JT allows examination of the contribution of genes on the Y chromosome to sexually dimorphic autosomal gene expression
Collaborator Contribution Obtaining genetically altered mice to analyse for effects on sexually dimorphic gene expression is enabling the molecular dissection of how in early deveelopment heterochromatin components have a dimorphic effect.
Impact Work in progress
Start Year 2016
 
Description MP 
Organisation Brunel University London
Department School of Health Sciences and Social Care
Country United Kingdom 
Sector Academic/University 
PI Contribution We analysed the mice for histone modifications at the Frataxin locus to determine the molecular pathogenesis underlying the aberrant silencing which results in the disease
Collaborator Contribution Provision of human frataxin transgenics providing mouse model of Friedreich's ataxia
Impact The data is in preparation for publication but has partly seeded an MRC DPFS grant
 
Description MU 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom 
Sector Academic/University 
PI Contribution PI cosupervised a student to extend an existing project initiated in our lab on Parkinson's disease using murine models
Collaborator Contribution Provided neurophysiological expertise to co-supervise a PhD student
Impact We have discovered a specific ion channel which functions abnormally in genetic mouse models of Parkinson's Disease leading to increased vulnerability of the neuron. This is therefore a potential novel therapeutic target.
 
Description NICOFA -E-rare funding for randomised controlled study for nicotinamide in Friedreich's ataxia 
Organisation University Hospital Aachen
Country Germany 
Sector Hospitals 
PI Contribution We have discovered that the aberrant gene silencing that occurs in Friedreich's ataxia causing the disease can be overcome in patients. This suggests that long-term treatment with nicotinamide would be expected to ameliorate disease progression in this frequently devastating and, so far, incurable disease. This study which was published in the Lancet has seeded further collaborations across EUrope to secure enough patients for a placebo controlled study.
Collaborator Contribution The partners have secured funding from a transnational E-rare funded collaboration. We are seeking funding from the MRC/NIHR EME scheme to fund the UK arm of the controlled trial.
Impact E-rare funding granted. EME proposal - full proposal invited.
Start Year 2016
 
Description WR 
Organisation Babraham Institute
Country United Kingdom 
Sector Private 
PI Contribution We generated transgenic murine model to demonstrate that the direct repeat associated with the Igf2 locus could initiate heterochromatin-formation at multiple sites in the mouse genome.
Collaborator Contribution We investigated the heterochromatin-nucleating properties of a densely methylated DNA repeat sequence associated with the Igf2 locus disscovered at Babraham
Impact We discovered that the balance between chromatin modifiers can regulate the distribution of the silencing machinery in the nucleus in vivo in mammals
 
Description X-inactivation 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaborating on the hypothesis that the inactive X-chromosome might be attracting heterochromatin proteins and thereby regulating sexually dimorphic gene expression
Collaborator Contribution We have discovered a hitherto hidden layer in the regulation of sexual dimorphism in gene expression at the epigenetic level. We are using a model system developed by our collaborator to gain insight into the molecular mechanism
Impact The research is in progress with no direct outcomes yet.
Start Year 2017
 
Title Identified potential therapeutic targets and therapies for Friedreich's ataxia 
Description We have found that particular histone deacetylase inhibitors can upregulate the aberrantly silenced Frataxin gene which is repressed in Friedreich's ataxia. 
IP Reference  
Protection Protection not required
Year Protection Granted 2008
Licensed No
Impact This has resulted in ourselves and opthers developing novel therapeutics which are undergoing testing in mouse models for Friedreich's ataxia.
 
Title HDACi 
Description Having shown that the GAA-triplet repeat expansion which occurs in the neurodegenerative disease, Friedreich's ataxia, can induce heterochromatin-mediated silencing we identified histone deacetylase inhibitors that can overcome such silencing in cells from patients. This has recently been tested in a proof-of-concept study (Libri et al Lancet 2014) 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2014
Development Status Actively seeking support
Clinical Trial? Yes
Impact We are investigating this finding as a potential treatment with help from an MRC DPFS grant and support from Ataxia UK and the EU FP7 programme. 
URL https://clinicaltrials.gov/show/NCT01589809
 
Title HDACi therapy for FRDA 
Description Identification of an HDAC inhibitor that can upregulate Frataxin in cells from patients with Friedreich's ataxia 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2012
Development Status Under active development/distribution
Impact Potential as a therapeutic for Friedreich's ataxia which is currently incurable 
 
Description Epigenesys Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited speaker at European Network to present novel results showing that a key component of heterochromatin is essential for sex differences very early on in development
Year(s) Of Engagement Activity 2016
 
Description Epigenomics of Common Diseases Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation of the finding that a major epigenetic regulator is crucial for regulating sexual differences before sex hormones kick in.
Year(s) Of Engagement Activity 2016
URL http://conf.hinxton.wellcome.ac.uk/advancedcourses/ECD2016Programme.pdf
 
Description Presentation at Gordon Conference in Chromatin Structure and Function 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Forum for experts in the field of chromatin and gene regulation to exchange unpublished data in order to further excellence in Science. This is a competitive leading conference in the field.
Year(s) Of Engagement Activity 2016
 
Description TV documentary 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Interviewed for EU funded TV documentarty on Epigenetics

Communicated key ideas to a large lay audience
Year(s) Of Engagement Activity 2009
 
Description TV-interview Dublin 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Interviewed at International conference for Friedreich's Ataxia

Raised the profile of the need for research in triplet-repeat diseases
Year(s) Of Engagement Activity 2008
 
Description Webinar Ataxia UK 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Triggered many questions and comments relating to the next stage of our research

After the webinar I was given advice from experts on how to conduct a clinical trial for efficay of our novel treatment for Friedreich's ataxia
Year(s) Of Engagement Activity 2014