23 Feb 2018

Exploring the brave new world of the epigenome

Professor Sam El-Osta's (second from right, back row) research group
by Anne Crawford

When it comes to the epigenome, there is a fine line between clarity and confusion—walk that line and you will discover another fascinating level of transcription control.

So begins a review of the current state-of-play of studies into epigenetics in diabetic complications led by Professor Sam El-Osta from Monash University’s Department of Diabetes. The paper, which focusses particularly on the complication diabetic nephropathy (kidney disease), appeared on the cover of last month’s edition of ‘Diabetologia’.

Epigenetic regulation, the inherited chemical modifications that affect DNA, brings a layer of complexity to the genetic code that poses a formidable challenge to efforts by scientists to decode the mechanisms underlying complex disease, the paper writes. However, increasingly accessible technologies, and computational advances, have improved understanding of the intricate chromatin landscape – the array of DNA, RNA and proteins found in cells – in the occurrence and progression of complex diseases.

Recent scientific literature – the study reviews 155 papers – demonstrates “immense potential” for epigenetics to explain many aspects of diabetic vascular complications.

Both type 1 and type 2 diabetes mellitus are associated with vascular complications, whether macrovascular complications such as myocardial infarction and stroke – the leading causes of morbidity and premature mortality in the diabetic population – or microvascular complications manifesting as retinopathy, neuropathy and nephropathy. People with diabetic nephropathy have an exceptionally high risk of cardiovascular disease.

Yet genetics alone does not explain why some individuals with diabetes are predisposed to developing vascular disease and are more likely to progress to advanced stages of complications and/or develop other associated vascular pathologies, the paper says. Epigenetics may be able to provide an explanation.

The epigenome is rich in therapeutic opportunity, the paper says. Compounds that target epigenetic pathways are increasingly being investigated pre-clinically, and drugs that are already used in clinical management of diabetes may impact the epigenetic landscape.

“Diabetes is a disease of our time, and, if there was a time to ‘never, never, never give up’ on epigenetics that time would be now,” said Professor El-Osta, the review’s senior author.

As well as being an exploration of the area, the review offers a hypothesis about a codified signature of the diabetic epigenome, with examples of candidates for chemical modification. “This signature controls some of the most critical nuclear events early in the development of diabetes,” Professor El-Osta said.

The study surveys future strategies to expedite and refine the search for pharmacological control of epigenetic marks and clinically relevant discoveries, and considers the challenges associated with therapeutic strategies targeting epigenetic pathways.

Professor El-Osta said interest in epigenetics and metabolic disease was increasing and that this was reflected by the organisation of the prestigious Gordon Research Conference on the topic to be held in Hong Kong on 27 May 27 to 1 June this year.

The ‘Epigenetic Mechanisms and Their Role in the Development of Diabetes’ conference – the first of its type – brings together world-leading authorities in epigenetics and diabetes, including speaker Professor Paul Zimmet AO, Professor of Diabetes at Monash University. It is co-chaired by Professor El-Osta and has Professor Mark Cooper AO, Head of the Department of Diabetes at Monash as a vice-chair.

The review was supported by the NHMRC and NSFC (National Science Foundation China). First author and collaborator was Monash alumni Dr Samuel Keating from the Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.

Keating ST, van Diepen JA, Riksen NP, El-Osta A. Epigenetics in diabetic nephropathy, immunity and metabolism. Diabetologia. 2018 Jan;61(1):6-20. doi: 10.1007/s00125-017-4490-1. Epub 2017 Nov 11.

For information about the conference go to:

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