Metabolic memory for atherosclerosis is mediated by epigenetic modifications in the bone marrow

Abstract

Epigenetic modifications are one of the most important means for control of gene activity; in essence to store, retain, and recall past experiences in a way to shape present and future behaviour. Over the last decade we have characterised the key epigenetic changes imprinted following exposure to high glucose levels. In addition, we have shown that this epigenetic programming directly contributes to persistent up-regulation of pro-inflammatory pathways by hyperglycaemia in both cells, animal models and in humans, in what has become known as 'metabolic memory'. This key discovery may partly explain the sustained 'legacy' of beneficial effects arising from improved glucose control in patients with diabetes, as well as contributing to the irreversible legacy of vascular damage, as has been observed in failed clinical trials of glucose lowering in patients with longstanding diabetes. We propose that the "legacy" of hyperglycaemia is partly mediated through epigenetic programming that promotes sustained activation of pathogenic pathways.While a functional legacy of prior hyperglycaemia with respect to atherosclerosis certainly exists, it remains to be established exactly where it resides. Recent studies have described the key mechanisms that contribute to the proliferation and expansion of bone marrow myeloid progenitors leading to increased circulating monocyte levels and subsequent accelerated recruitment into vessel walls of these cells in diabetes and in obesity. Given the key role of monocyte recruitment and adhesion to the atherosclerotic lesion in plaque development, resolution and stability/vulnerability we hypothesise that metabolic memory resides in the progenitor cells of the bone marrow. In the proposed research project, we aim to validate this hypothesis by: 1. Defining the epigenetic modifications induced by glucose exposure in haematopoietic stem and multi-potential progenitor cells (HSPCs) and exploring their interaction with gene expression by comparing epigenetic signatures with whole transcriptome analysis. 2. Transplanting 'imprinted' bone marrow from diabetic animals to explore its legacy in non-diabetic mice. 3. Characterizing gene regulatory mechanisms conferring metabolic memory and the potential for modification of these effects by pre-treatment with epigenetic modifiers.Significance and Innovation. The effective prevention and management of cardiovascular disease (CVD) is an important national health priority. Current diabetes management is insufficient to prevent metabolic memory. We hypothesise that understanding epigenetic programming as a result of hyperglycaemia will lead to the identification of novel biomarkers as well as new targets for the prevention and treatment of CVD particularly in the setting of diabetic complications.Feasibility. This proposal builds on the skills and experience of an internationally-competitive team based at Central Clinical School at Monash University. Prof El-Osta is an epigeneticist that brings technological expertise and state-of-the-art analyses for epigenomic studies including sequencing combined with contemporary ChIP platforms. Prof Thomas brings skills in diabetes complications, while the Dr Murphy is an expert in atherobiology. Prof Mark Dawson has pioneered the generation of immortalized primary mouse HSPC lines. Thus, the proposed studies are within their qualifications as reflected by the quality of the pilot data presented below, as well as state-of-the-art methodology and highest-quality papers published by the application team.