CCT/Nehru Memorial Trust studentship: Histone H3 lysine 9 demethylation in cardiac hypertrophy

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

Heart disease is a significant cause of mortality in the developed world. In 2004 it was responsible for 137,700 deaths in the UK, equating to 24% of all deaths. A major predictor of mortality due to heart disease is cardiac hypertrophy (an increase in cell size without increase in cell number), and it is the most important risk factor for heart failure in humans. Hypertrophy can however also be a beneficial adaptive response providing the increased blood supply required during pregnancy and to sustain levels of increased physical activity experienced by athletes. Cardiac hypertrophy is characterised by an increase in the muscle mass/size of the heart due to enlargement of heart cells without any proliferation. This increase in heart size is caused by a significant change in the expression levels of a number of genes (the copying of DNA information into RNA and then often into protein) - some are upregulated whereas the expression of other genes is decreased. This remodelling of gene expression is controlled by factors (transcription factors) that bind to the DNA as well as by proteins that modify the structure and packaging of DNA. In genes that are active, the DNA is in an open conformation allowing access to transcription factors that cause the induction of gene expression. To inhibit gene expression, DNA is modified in a way to decrease its accessibility to these transcription factors. In this study, we plan to investigate these mechanisms that control suppression of gene transcription. In particular, the role of enzymes responsible for the de-methylation of the histone proteins around which the DNA is wrapped will be studied. We will also plan to identify how changes in the environment, associated with hypertrophic stress, signal to these histone modifying enzymes to control activity.

Publications

10 25 50
publication icon
Thienpont B (2017) The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophy. in The Journal of clinical investigation

 
Description in response to different stresses, the heart grows. This may be as a result of diseases such as myocardial infarction, as a result of chronic exercise or pregnancy. Although heart growth in response to the physiological stimuli is beneficial, when induced by disease, the heart growth is no beneficial and is often a prequel to heart failure - when the heart cannot provide for the body.
In this project we analysed manipulation of the epigenome - the way DNA is packed and regulated in a cell - were altered by enzymes called histone demethylases.
We found that these proteins had a complicated role in the heart and could enhance expression of genes associated with maladapted cardiac growth.
they project was linked with another in the laboratory and contributed to establishing the role of particular modification of DNA structure that regulates gene expression in determining cardiac growth responses to pathological vs physiological stress. This work is now published.
This was a student project. The student successfully completed her PhD.
Exploitation Route The work remains to be published but will no doubt identify new ways by which heart growth and cell division can be manipulated to enhance function.
Sectors Pharmaceuticals and Medical Biotechnology

URL https://www.jci.org/articles/view/88353
 
Description Odysseus FWO
Amount € 837,974 (EUR)
Funding ID 90663 
Organisation Research Foundation - Flanders (FWO) 
Sector Charity/Non Profit
Country Belgium
Start 10/2014 
End 09/2019
 
Description Norway Rats 
Organisation University of Oslo
Department Institute for Experimental Medical Research
Country Norway 
Sector Academic/University 
PI Contribution Analysis of Cardiac Myocyte proteome, transcriptome and epigenome.
Collaborator Contribution Provision and phenotyping of hearts hypertrophic due to exercise, aortic banding or ageing.
Impact Publication in JCB in 2012 27893464 23166348
Start Year 2009
 
Description Nuclear Isolation 
Organisation Karolinska Institute
Department Department of Cell and Molecular Biology
Country Sweden 
Sector Academic/University 
PI Contribution Analysis of transcriptome and epigenome of human cardiomyocyte nuclei
Collaborator Contribution Provision of nuclei from human cardiac myocytes
Impact 27893464
Start Year 2010
 
Description Late nite lab 2012 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Adults attended an open evening with talks and exhibits from scientific departments from the Cambridge area. Our research was explained and science in general discussed during a drinks reception.

Several parents asked for guidance regarding scientific careers for their children
Year(s) Of Engagement Activity 2012
 
Description Royal Society Summer Exhibition 2012 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact NA
Year(s) Of Engagement Activity 2012