Ewch i’r prif gynnwys
Vincent Dion

Yr Athro Vincent Dion

Professor, Dementia Research Institute

Yr Ysgol Meddygaeth

Email
DionV@caerdydd.ac.uk
Telephone
+44 29225 10893
Campuses
Adeilad Hadyn Ellis, Ystafell 1.03 - Office J, Heol Maendy, Caerdydd, CF24 4HQ
Users
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Trosolwyg

We are interested in gene editing and epigenome editing for expanded CAG/CTG repeats. These unusual sequences cause 13 different neurological disorders, including Huntington's disease and myotonic dystrophy. They all remain without effective treatments. We are looking for novel and innovative therapeutic avenues.

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Ymchwil

Expanded CAG/CTG repeats cause over 13 neurological and neuromuscular disorders, including Huntington disease, myotonic dystrophy, and several spinocerebellar ataxias. The diseases are debilitating, often leading to dementia. There is no available cure. Individually expanded repeat disorders are rare but together account for about 1 in 2000 people worldwide.

Our goal is to develop novel therapeutic avenues by targeting the unique features of expanded CAG/CTG repeats and to develop new technologies to detect (i.e., diagnose) and manipulate them. To achieve this, we use a variety of tools, including cutting edge molecular biology and genome engineering technologies, next-generation sequencing, as well as in vitro and in vivo pre-clinical disease models.

My laboratory has three main focal areas:

1) Gene editing and the mechanism of expanded CAG/CTG repeat instability

Expanded CAG/CTG repeats are highly unstable somatically, leading to mutation frequencies of 100% in some tissues. The size of the repeat tract determines in large part the severity of the disease. Understanding this mechanism is essential to designing and optimising treatments aimed at contracting the repeat tract.

We have recently developed a gene editing-based approach to contract the expanded repeat tract using the CRISPR-Cas9 system. We are currently determining whether this technology is applicable to contract and slow, prevent, or reverse the disease phenotypes in cells and in vivo. Moreover, we are studying the mechanisms of repeat contraction with the aim of improving the efficacy of inducing contractions.

Representative reference: Cinesi, C., Aeschbach, L., Yang, B. and Dion, V. (2016) Contracting CAG/CTG repeats using the CRISPR-Cas9 nickase. Nat Commun, 7, 13272.

2) The role of chromatin structure in the expression of expanded CAG/CTG repeats

Expanded CAG/CTG repeats accumulate chromatin marks reminiscent of heterochromatin and are downregulated (but not completely silenced) compared to normal size repeats. In addition, there is genetic and biochemical evidence that expanded repeats require extra factors for efficient expression. Identifying these factors and identifying their mode of action may lead to the development of epigenome editing approaches to combat expanded CAG/CTG repeat disorders.

We have developed a novel inducible chromatin targeting assay that allows us to determine which factors can change gene expression of expanded CAG/CTG repeats specifically. With this method, we can start to uncover a way forward to silence expanded repeats specifically.

Reference: Yang B, Borgeaud A, Aeschbach L, Dion V. (2018) Uncovering the interplay between epigenome editing efficiency and sequence context using a novel inducible targeting system. BioRxiv.

Moreover, changes in chromatin marks is often associated with changes in higher order folding. We tested the prevalent hypothesis the expanded CAG/CTG repeats change chromatin folding, which impinges on repeat instability, changes in gene expression, and pathogenesis of Huntington's disease and myotonic dystrophy type 1. Using both molecular biology and bioinformatics, we find that this is not the case.

Reference: Ruiz Buendía G, Leleu M, Marzetta F, Vanzan L, Tan JY, Marques AC, Baubec T, Murr R, Xenarios I, Dion V. Three-dimensional chromatin interactions remain stable upon CAG/CTG repeat expansion. BioRxiv

3) Development of tools to manipulate and detect expanded CAG/CTG repeats

Determining repeat size for diagnostic purposes and for routine molecular biology applications is laborious. This is because of the repetitive nature and the inherent heterogeneity of the repeat size from cell to cell (i.e., repeat instability). Thus, there is a great need to improve on the current technologies. In addition, such system will help us determine whether any therapies involving contracting the repeat tracts are effective.

Towards these goals, we are developing, in collaboration with the laboratory of Aurélien Bancaud (LAAS, France), microfluidics-based technologies for sizing expanded repeats. In addition, we have an ongoing collaboration with Ioannis Xenarios (UNIL, Switzerland) to develop sequencing-based approaches for these purposes.

Representative reference: Malbec R, Chami B, Aeschbach L, Ruiz Buendía GA, Socol M, Joseph P, Leïchlé T, Trofimenko E, Bancaud A, Dion V. (2019) µLAS: Sizing of expanded trinucleotide repeats with femtomolar sensitivity in less than 5 minutes. Scientific Reports 9, (1):23.

Bywgraffiad

Vincent Dion started his scientific career in 1999 as a summer student in Stanley L. Miller’s laboratory at UCSD (USA). He also spent time as an undergraduate in the laboratories of Benoit Chabot and Reymund Wellinger at the University of Sherbrooke (Canada). He completed his B.Sc. in molecular biology and genetics in 2002 at the University of Guelph (Canada) with a honours thesis supervised by David H. Evans. In 2007, he obtained his PhD from Baylor College of Medicine (USA), under the supervision of John H. Wilson, for defining the role of DNMT1, the maintenance DNA methyltransferase, in preventing disease-causing CAG/CTG repeat expansions. As a postdoc with Susan M. Gasser at the Friedrich Miescher Institute (Switzerland), he discovered a novel role for chromatin remodeling enzymes in the repair of deleterious DNA double-strand breaks. He joined the Center for Integrative Genomics at the University of Lausanne (Switzerland) in 2013 on a professorship from the Swiss National Science Foundation. He became Professor at the UK Dementia Research Institut at Cardiff University in January of 2019. His lab has made key contributions towards the development of gene editing approaches to correct mutations that cause 14 different neurological, neuromuscular, and neurodegenerative diseases, which all remain without a cure.

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How to apply

Open positions will invariably be posted here.
Outstanding prospective PhD students and Postdocs who have or can attract their own fellowships are always welcome and should contact me.
Talented undergraduates and Master students are also welcome - contact me directly.

Guidelines to writing a cover letter for prospective PhD and postdocs

The goal of a cover letter is to convince the group leader to open your CV. No more, no less. Consequently, you need to keep it short (~250 words or less) and to the point. People are more likely to read something short. Your letter must contain the answer to two big questions:

  1. Why are you interested in this particular lab? This has to be as precise as possible. Broad answers to this questions, for example stating that you “want to join an outstanding institution”, are not compelling. Be specific. Why are you interested in our lab and not the lab next door? Why is the topic of the lab interesting to you? In other words, I want to know why you are applying to my lab and that you are not simply sending mass e-mails hoping that something will stick.
  2. What do you bring to the lab? This can be knowledge of a specific technique or field. Listing the techniques you are familiar with is not necessary as they should be in your CV, makes your cover letter longer, and generally does not help your case. Another way of phrasing this question is “What makes you stand out and be particularly well suited to join the lab?” It is not a problem if your area of expertise is outside that of the lab – it can be an advantage. But then you will have to emphasize why you are applying, which brings you back to why you are interested in this particular lab.

Some more tips:

  • Make the letter personal and custom-tailored. A good way to make the letter stand out is to explain the research topic of the lab in your own words. You will have to do it well (and briefly), however, as it can backfire if not done properly. Do not copy and paste from the lab’s website or papers.
  • Start the letter with why you are writing. Often letters start with “I am So and So from University X”. This is superfluous information as it is at the bottom of the e-mail and/or in your CV.
  • Writing a letter free of typos and grammatical mistakes is a good way to make a good first impression. Avoid overly flowery language (e.g., Dear Esteemed Sir) and using “Greetings” as an opening.
  • A specificity of Cardiff University is that if you are responding to a job advert, the job descriptions are divided into essential and desirable criteria. To obtain an interview you have to meet all the essential criteria. In your cover letter, list the essential criteria and explain how you meet them. It does not hurt to do so for the desirable criteria also. This makes the shortlisting easier and increases your chances of getting an interview. This part does not count towards the ~250 word guideline above, but it helps to keep it consice.

Quality and care in a letter will take you time, but it will make an enormous difference: many fewer requests will go unanswered. Remember that top labs want to hire passionate, motivated, and hard-working people. A well written letter should convey that you possess these qualities!

Ymchwilydd o Gaerdydd yn ennill proffesoriaeth fyd-eang

Ymchwilydd o Gaerdydd yn ennill proffesoriaeth fyd-eang

31 October 2019

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