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Winter 2017

A change of heart: epigenetic basis of disease heart growth uncovered

Copyright: Hanneke Okkenhaug, Babraham Institute and Llewelyn Roderick, KU Leuven
News from: The Babraham Institute

The heart is an amazingly adaptable organ, responding to the needs of the organism throughout life, such as through periods of increased demand by pumping harder, faster, and also growing to accommodate longer-term requirements such as that experienced in pregnancy or as a response to intense exercise.

Some cardiac diseases, such as prolonged high blood pressure and heart attacks, also cause an increase in the heart’s muscle mass but dangerously this results in a reduction in cardiac output and can cause an irregular heart rhythm. This growth is called pathological cardiac hypertrophy and eventually leads to heart failure and death. Cardiovascular diseases account for a third of all deaths in the UK.

Researchers at the Babraham Institute, which receives strategic funding from BBSRC, the University of Leuven, Belgium, University of Oslo, Norway and Karolinska Institute, Sweden, have uncovered the molecular control mechanisms responsible for the different biological changes seen in cardiac hypertrophy induced by pathology compared to exercise. These findings point the way for the design of new treatments for heart disease.

Their research, published in the Journal of Clinical Investigation, compared the differences between hypertrophic heart growth in rats as a result of exercise – which is beneficial – and heart growth induced by pathology – in this case, increased load. Specifically, they compared epigenetic marks responsible for locking cells in their final developed state – important for preventing cells from switching to a less differentiated state. Notably for their analysis, the researchers employed a powerful cell sorting technique to allow them to study pure populations of heart muscle cells (cardiomyocytes) rather than a mix of all cell types in the heart – which, due to an alteration in composition during disease, would confound analysis.

They found a mechanism explaining how, in the case of pathological cardiac hypertrophy, cardiomyocytes lose their adult cellular state and regress back towards their foetal form, switching on genes that were originally expressed as the heart develops in the embryo and usually permanently switched off after birth.

Professor Wolf Reik, Head of the Epigenetics Programme at the Babraham Institute, said: “We found that a very important repressive methylation mark is lost by cells in cardiac hypertrophy. The function of this mark is to lock adult cardiomyocytes in their adult state. The loss of the mark leads to inappropriate gene expression as shown by the re-expression of genes usually only seen late in embryo development.”

Copyright: Hanneke Okkenhaug, Babraham Institute and Llewelyn Roderick, KU Leuven
Copyright: Hanneke Okkenhaug, Babraham Institute and Llewelyn Roderick, KU Leuven

The research also analysed human cardiomyocytes and importantly the same molecular changes were seen, demonstrating that the same epigenetic factors underlie cardiac hypertrophy and disease remodelling in humans.

Professor Llewelyn Roderick, former group leader at the Babraham Institute, now Professor in the Department of Cardiovascular Sciences at KU Leuven, commented: “Our research has defined a novel epigenetic-based mechanism which explains the contrasting outcomes of cardiac remodelling caused by exercise and pathology. By identifying the epigenetic determinants and the responsible epigenetic enzymes controlling these different forms of cardiac myocyte hypertrophy, as well as how the epigenetic modifiers are themselves regulated by micoRNAs, we provide a potential strategy for epigenetic therapy for adverse cardiac remodelling. This work highlights the value of collaborative research to allow analysis from physiology to molecule and back again’.

This work was funded by the BBSRC which provides strategic support to the Babraham Institute, The Royal Society and an Odysseus award from the Research Foundation Flanders FWO to support the aspects of this work undertaken at the Babraham Institute. The collaborative work at the University of Oslo was supported by the KG Jebsen Cardiac Research Center and the Center for Heart Failure Research of the University of Oslo and by the Anders Jahres Fund for the Promotion of Science. At the Karolinska Institute, the work was supported by the Swedish Research Council, the Ragnar Söderberg Foundation, the Jeansson Foundations, and the Åke Wibergs foundation.

ENDS

Notes to editors

Publication reference: Thienpont, Aronsen, Robinson et al. (2016) The H3K9 dimethyltransferases Ehmt1/2 protect against pathological cardiac hypertrophy. Journal of Clinical Investigation. https://doi.org/10.1172/JCI88353

Header image description: Microscopic image of rat heart tissue, displayed in a heart-shaped window. The red shapes are the nuclei of cardiomyocyte cells, blue show nuclei from other heart cell types. The pink striped areas identify proteins involved in contraction. Copyright: Hanneke Okkenhaug, Babraham Institute and Llewelyn Roderick, KU Leuven.

About the Babraham Institute

The Babraham Institute, which receives strategic funding (a total of £21.2M in 2015-16) from the Biotechnology and Biological Sciences Research Council (BBSRC), undertakes international quality life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. The Institute’s research provides greater understanding of the biological events that underlie the normal functions of cells and the implication of failure or abnormalities in these processes. Research focuses on signalling and genome regulation, particularly the interplay between the two and how epigenetic signals can influence important physiological adaptations during the lifespan of an organism. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and healthier ageing. www.babraham.ac.uk

About VIB

Basic research in life sciences is VIB’s raison d’être. On the one hand, we are pushing the boundaries of what we know about molecular mechanisms and how they rule living organisms such as human beings, animals, plants and microorganisms. On the other, we are creating tangible results for the benefit of society. Based on a close partnership with five Flemish universities – Ghent University, KU Leuven, University of Antwerp, Vrije Universi0eit Brussel and Hasselt University – and supported by a solid funding program, VIB unites the expertise of 75 research groups in a single institute. VIB’s technology transfer activities translate research results into new economic ventures which, in time, lead to new products that can be used in medicine, agriculture and other applications. VIB also engages actively in the public debate on biotechnology by developing and disseminating a wide range of science-based information about all aspects of biotechnology. www.vib.be/en

About KU Leuven

Founded in 1425, the University of Leuven (KU Leuven) has been a centre of learning for almost six centuries. Today, it is Belgium’s largest and highest-ranked university as well as one of the oldest and most renowned universities in Europe. As a leading European research university and co-founder of the League of European Research Universities (LERU), KU Leuven offers a wide variety of programmes in English supported by high-quality interdisciplinary research. Boasting an outstanding central location in the heart of Europe, KU Leuven offers a truly international experience, high-quality education, world-class research and cutting-edge innovation.

About BBSRC

BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.

Funded by government, BBSRC invested £473 million in world-class bioscience, people and research infrastructure in 2015-16. We support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.

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