The role of chromatin remodelling factors in cerebellar development and autism

Lead Research Organisation: King's College London
Department Name: Craniofacial Dev Orthodon and Microbiol

Abstract

Autism can be a devastating condition for which no suitable treatment exists. Autism affects some of the core behavioural features an individual needs to function in society, namely social interaction and both verbal and non-verbal communication. Children affected by autism often demonstrate restricted, repetitive patterns of behaviour and interests. The number of individuals diagnosed with Autism Spectrum Disorder (ASD) has increased dramatically over the last decade and current estimates suggest that up to 1/110 of the population may be affected. The causes of autism are not known and without this knowledge, there is limited hopes of finding novel ways of treating this condition or improving the lives of autistic children.

Autism is a complex genetic condition; many genetic abnormalities that can predispose a child to autism have been identified, but our knowledge on how these genetic risk factors can cause changes during brain development to result in autistic behaviour is extremely limited. Studies in autistic children have suggested that the growth of certain parts of the brain might to be altered during development. The part of the brain that appears to be affected most often is the cerebellum. The cerebellum controls movement, but also functions as an important modulator of other parts of the brain, including regions involved in social cognition and language development. It is not known how these defects in the cerebellum arise, nor is it known what the effects of cerebellar defects are on behaviours characteristic of autism. Currently, the best way to address this question directly is to study brain development and the behavioural consequences of altered brain development on behaviour in mice that have mutations in autism-associated genes.

Our group have been investigating the functions of the CHD7 gene in brain development. CHD7 causes CHARGE syndrome when mutated, a complex human syndrome where children suffer from a range of birth defects in addition to autistic symptoms. We recently identified essential roles for CHD7 in the development and growth of the cerebellum. When CHD7 is mutated, we observe defects in specific areas of the cerebellum that have been linked to autism. The aim of this project will be to identify the exact causes of these defects and to uncover the specific processes that are defective when CHD7 is absent. This knowledge may help define specific therapies to target these processes in the future.

In addition, we have used the powerful genetic methods available in the mouse to produce mutants in which CHD7 is removed specifically from the developing cerebellum. These new mouse mutants will enable us to determine to what extent these cerebellar defects cause autistic symptoms. Furthermore, we will take the same approach to determine the function of a related gene called CHD8, which was recently shown to be very strongly associated with autism in the human population, but without any of the birth defects typical of CHARGE syndrome. These studies will allow us to hone in on the specific causes of autism.

This research will allow us to find answers to several important questions in autism research. We will identify the reasons why mutations in CHD7 and CHD8 can cause problems during brain development, the exact mechanisms whereby these factors control growth and development of the cerebellum and we will determine to what extent cerebellar defects are responsible for some of the core behavioural symptoms characteristic of autism. Taken together, our research will significantly improve our understanding of the causes of autism and define the importance of cerebellar defects in the development of autism. Our findings will create an important source of knowledge upon which future attempts to predict, diagnose, and possibly treat specific aspects of autism could be based.

Technical Summary

Autism is a complex genetic disorder that affects social development. Recent advances have led to the identification of several autism-associated genes. This proposal will examine the neurodevelopmental role of two of these genes, the chromatin-remodelling factors CHD7 and CHD8. CHD7 is mutated in CHARGE syndrome, which is a syndromic form of autism. We have recently produced new mouse models that reveal key functions of CHD7 in the development of the cerebellum, a part of the brain that is consistently reported to show neuro-anatomical defects in autistic patients. We will use these mouse models to test important questions about the relationship between the genetic control of cerebellar development and autism. First, we will determine the developmental and epigenetic mechanisms that underlie these cerebellar defects. Second, we will use mouse models in which CHD7 is specifically deleted from the developing cerebellum to test to what extent cerebellar defects are responsible for some of the behavioural features characteristic of autism; a critical question remaining in the field. We will build on this model to explore the significant association of CHD8 haploinsufficiency with non-syndromic autism. CHD7 and CHD8 proteins directly interact and our preliminary studies suggest that CHD8 and CHD7 might regulate similar pathways during cerebellar development. To define the mechanisms whereby CHD8 deficiency causes autism, we will identify the functions of CHD8 in brain development and determine the behavioural consequences of CHD8 deletion from the developing cerebellum. Together, these studies will identify new epigenetic mechanisms that can cause cerebellar defects and determine the consequences of cerebellar hypoplasia, in the absence of primary defects in the neocortex, on behaviours characteristic of autism.

Planned Impact

A key component of our proposal is the assertion that specific cerebellar defects caused by mutations in chromatin remodelling factors are responsible for some of the behaviours characteristic of autism. As such, our research has the potential to benefit a range of clinical researchers and health professionals, students, patient and family groups. The knowledge of mechanisms that underlie autism to be gained in this study, may lead to the development of effective treatments and interventions that will have significant economic benefits by allowing people affected by autism to fully integrate in society and contribute to the economy.

Clinical research: In the short term, our research will have the most immediate impact on academic and clinical researchers interested in neurodevelopmental disorders. In particular, clinical researchers interested in the causes of autism and the role of the cerebellum in autistic behaviours, are likely to benefit from our studies, especially if we find strong evidence for cerebellar involvement in behaviours like social cognition, communication, repetitive behaviours and cognitive rigidity. Our findings are likely to stimulate further clinical research studies and trials to assess cerebellar defects in autistic patients and children deemed at risk of developing autism. A potential longer-term effect of our research that can be foreseen, is the development of improved methods for detecting alterations in cerebellar structure (e.g. by MRI) and connectivity (fMRI) that could be applied to screening and diagnosis.

Health professionals and patient groups: Eventually, in the longer term, our studies might be translated to the clinical setting where they will impact on approaches for the diagnosis and screening of patients. An improved understanding of the critical parts of the brain associated with particular autistic behaviours, and the underlying molecular mechanisms that can cause autism will be beneficial for patients, families and genetic counsellors.

Potential economic impacts: In the long-term, our findings might lead to the design and evaluation of specific treatments or therapies that target epigenetic processes to improve or alter relevant neuronal functions or processes. Although still a long way off, this study will begin to identify some of the epigenetic mechanisms that underlie phenotypes associated with autism, which could form the basis of further translational research.

Potential societal impacts:
Students and teaching: Applicants provide several lectures on epigenetics, neurodevelopment and disease and behaviour to undergraduate students at King's College London. The quality of these lectures is substantially improved by the use of topical examples from our research.

Basson contributes to outreach activities at King's College, in particular by lecturing on the Worshipful Company of Barbers' Science and Medicine in Action lecture series for 6th form students considering a career in the health sciences. The most popular lecture is one that examines the use of model organisms to dissect the mechanisms that control brain development and to study the causes of conditions like CHARGE syndrome and autism. Students are encouraged to think about the value of research and creation of knowledge in this lecture, a somewhat different approach than the other lectures that focus on clinical practice.

Wider public: Where appropriate, we strive to maximise the wide dissemination of our research to reach the wider public. This project, which aims to address several compelling and important questions about the causes of autism and behaviours inherently of great interest such as language and social interactions, has significant potential for public engagement. Wingate has a particularly strong history in public outreach in the art-science sector and will use his established networks to disseminate our research findings.

Publications

10 25 50
 
Description MRC project grant
Amount £636,198 (GBP)
Funding ID MR/N000528/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2016 
End 12/2018
 
Description MRC project grant
Amount £568,000 (GBP)
Funding ID MR/R004625/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 02/2018 
End 01/2021
 
Description PhD studentship
Amount £78,000 (GBP)
Organisation Anatomical Society 
Sector Learned Society
Country United Kingdom
Start 10/2016 
End 09/2019
 
Description Pilot Award
Amount $49,270 (USD)
Organisation CHARGE Syndrome Foundation 
Start 10/2016 
End 08/2019
 
Description Pilot Award
Amount $250,000 (USD)
Funding ID 344763 
Organisation Simons Foundation 
Department Simons Foundation Autism Research Initiative
Sector Charity/Non Profit
Country United States
Start 09/2015 
End 08/2017
 
Description SFARI Explorer Award
Amount $60,000 (USD)
Organisation Simons Foundation 
Department Simons Foundation Autism Research Initiative
Sector Charity/Non Profit
Country United States
Start 05/2014 
End 04/2015
 
Title Chd8 mouse 
Description New Chd8 conditional mouse line 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2015 
Provided To Others? Yes  
Impact Will allow assessment of autism behaviours and associated phenotypes in vivo and dissect cell type-specific roles 
 
Description CHARGE syndrome 
Organisation University of Groningen
Country Netherlands 
Sector Academic/University 
PI Contribution Provide information on new findings in mouse models
Collaborator Contribution Provide information and material from CHARGE syndrome clinic e.g. MRI scans and other clinical information, DNA sequencing
Impact Publication: Yu et al. (2013) Elife
Start Year 2013
 
Description Chromatin Biochemistry 
Organisation Howard Hughes Medical Institute
Country United States 
Sector Charity/Non Profit 
PI Contribution Provide information on functional in vivo findings
Collaborator Contribution Expertise in chromatin biochemistry
Impact Publication: Yu et al (2013) Elife
Start Year 2013
 
Description Epigenetic mechanisms underlying hearing impairment 
Organisation King's College London
Department Craniofacial Development & Stem Cell Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided ear tissue from Chd7-deficient mice and expertise in chromatin and CHARGE syndrome
Collaborator Contribution Performed analysis of ear tissue and identified novel phenotypes and mechanisms that may underlie hearing impairment in CHARGE syndrome
Impact MRC Project Grant MR/R004625/1: 1/02/2018-31/01/2021 (10% time) Epigenetic mechanisms underlying hearing impairment A. Streit (PI), M.A. Basson (co-PI), M. Ahmed (co-PI) Total support: £567,926
Start Year 2017
 
Description Investigating genetic interactions between Tbx1, Chd7 and Fgf8 
Organisation University College London
Department Institute of Child Health
Country United Kingdom 
Sector Academic/University 
PI Contribution We provided genetically modified mouse lines not available elsewhere in Europe. These mice were crossed with mutant lines from the Scambler group and vessel phenotypes and gene expression analysed to determine whether these genes interact during vessel development. We also provided a Cre line which we imported from Japan and not available elsewhere.
Collaborator Contribution Provided expertise in the form of new techniques and insights, and new reagents which have enabled us to develop a new hypothesis, currently being tested.
Impact We have started a new project in collaboration following on from this, new hypotheses are currently being tested by two postgraduate students in my group, the outcome of which is expected to form the basis of a new grant application.
Start Year 2008
 
Description Rodent autism behaviours 
Organisation National Institute of Health
Country Italy 
Sector Public 
PI Contribution Produce new autism mouse models
Collaborator Contribution Student exchanges, collaborations to analyse ultrasonic vocalisations and developmental milestones
Impact Two PhD student exchanges from Italy to UK
Start Year 2014
 
Description Rodent rsfMRI 
Organisation Italian Institute of Technology (Istituto Italiano di Tecnologia IIT)
Country Italy 
Sector Public 
PI Contribution Provided new GM mouse model for rsfMRI
Collaborator Contribution Performed rsfMRI on a new mouse model of ASD
Impact Suetterlin et al. (2018) Cereb Cortex, in press
Start Year 2017
 
Description 6th form 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact Outreach to 6th form students interested in a career in biomedicine.
250 students attended my 1 hour lecture with 30min questions and discussion afterwards.
As a result of the positive feedback from students, I have been asked to provide a similar lecture again next year, and will be the only non-clinical scientist to do so.


As a direct result of my lecture, two students contacted me and visited my research group for 1-2 week periods for shadowing researchers and work experience.
One student successfully applied for a Nuffield Foundation Science Bursary and completed an 8-week research project in my laboratory over the summer.
Year(s) Of Engagement Activity 2011,2013
 
Description CHARGE family support group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presented our findings on cerebellar hypoplasia and ongoing research in brain abnormalities associated with CHARGE syndrome to the UK CHARGE family support group. Between 50-100 people were present consisting of professional practitioners (Clinical genetics, Psychiatry, deaf-blind teachers), carers, parents and patients. This activity raised awareness amongst the community for cerebellar and brain abnormalities in CHARGE and how investigating these may contribute to our understanding of a range of neurodevelopmental, psychiatric, behavioural ands learning issues associated with CHARGE syndrome.
Year(s) Of Engagement Activity 2018
URL https://www.eventbrite.co.uk/e/charge-syndrome-uk-conference-professionals-day-registration-46510535...
 
Description International Innovation 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Three-page article in International Innovation", a magazine with more than 51,000 readers, including government and EU policymakers, health professionals and the wider public.

Contacted by clinicians and policymakers interested in CHARGE syndrome
Year(s) Of Engagement Activity 2012
URL http://www.researchmedia.eu
 
Description Nuffield Foundation 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact Hosted and supervised a summer student for a 8 week period over the summer.

Student was awarded a gold and platinum award of excellence. Will continue providing these opportunities to 6th form students.
Year(s) Of Engagement Activity 2011,2012,2013,2014,2015
 
Description Patient group conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Plenary presentation at the international CHARGE syndrome foundation meeting. Attended by >100 people, comprising patients, parents and carers, professionals (teachers, educators, clinicians, scientists), students, foundation supporters and other scientists.
Year(s) Of Engagement Activity 2017
 
Description Research presentation 
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 - Simons Foundation Autism Research Initiative (SFARI) annual meeting. Presented our new findings on a CHD8 mosque model to autism researchers funded by SFARI and officials from the foundation.
Year(s) Of Engagement Activity 2016