The metabolically-induced epigenetic memory as a Regulator of myocardial stress response

点击翻译按钮获取中文摘要

Challenges for a personalized diagnostic and therapeutic approach to cardiac diseases are the interindividual differences in the course of the disease and the individually different risk factors. One risk factor for cardiac diseases is overweight and the associated systemic changes, which are summarized under the term 'metabolic syndrome'. In addition to the genetic preconditions that every patient inevitably brings with him/her, he/she goes through a number of phases in his/her life that promote illness or health (e.g. phases of obesity, smoking or extensive sporting activity). This individual history may influence the heart's reaction to future stress situations (e.g. catecholamines). A molecular mechanism of this observation has not yet been reliably proven in the heart. Epigenetic alterations can lead to modifications of pathological or protective genes, so that they behave differently in stress situations. A certain class of genomic regions, the enhancers, are of particular interest here. They not only regulate the transcription of one gene, but can also interact with multiple genes due to the 3-dimensional folding of DNA. Transcriptional activation is always preceded by enhancer activation, and can therefore be permanently altered without direct expression changes (or measurable clinical phenotype). In preliminary experiments, we have fed mice on a high-fat diet (HFD) and compared them with mice that underwent a change from HFD to a normal diet (HFLFD). Using chromatin immunoprecipitation of active enhancers, we identified a genomic region that is switched on in HFD-treated animals and remains switched on even if the phenotype (overweight) of the mouse returns to completely normal after switching from HFD to LFD (normal weight). This region contains two enhancers (metabolic enhancers 1 and 2; ME1/2) and a coding gene (Id1). Using CRISPR/Cas9 we have genetically deleted ME1 and ME2 as well as Id1 in cardiomyocytes (E1-cKO; E2-cKO. Id1-cKO). Conditional Id1 knockout mice show reduced cardiac function at the age of 4 months. It is unclear to what extent ME1 (or ME2) regulate the expression of Id1 and what consequences dysregulation of Id1 has in the adult heart under stress conditions. The aim of the present proposal is to further investigate the role of ME1 and ME2 for epigenetic memory in cardiomyocytes. Specific objectives are:1: Characterization of conditional knockout lines for E1-cKO, E2-cKO and Id1-cKO under high-fat diets and catecholaminergic stress.2: Identification of the proteo-genomic interaction partners of ME1 and ME23: Importance of epigenetic memory activation (ME1/2) in vivo for the response to catecholaminergic stress