Metastable Epiallele: Role of Epigenetic Variability for the Development of Metabolic and Endocrine Diseases

Introduction

The development of obesity in industrial and low-and middle-income countries is leading to a severe burden for patients and health care systems based on associated comorbidities such as cardiovascular diseases and type 2 diabetes mellitus.

Role of Epigenetics

Apart from the genetic background, epigenetic modifications like DNA methylation are supposed to play an important role in body weight regulation. So far, epigenome-wide association studies have not been able to elucidate this relationship, as most methylation differences were related to a genetic variant.

Importance of POMC Gene

Therefore, the identification of the POMC (pro-opiomelanocortin) gene, a key factor for hypothalamic body weight regulation, as a metastable epiallele in humans was of importance to understand how methylation variability affects the individual phenotype.

Characteristics of Metastable Epialleles

Metastable epialleles are methylome-regions that are:

• Non-genetically determined
• Stochastically regulated
• Set in early embryonic development
• Non-tissue specific
• Stable over time
• Modified by Carbon-1 metabolites in utero

However, their role in human diseases remains unclear.

Research Objectives

Within this application, I want to elucidate and characterize how epigenetic modifications, such as metastable epialleles, modulate human susceptibility and predisposition to metabolic and endocrine diseases and analyze the impact of environmental factors.

Proposed Methodology

To achieve this goal, I propose a unique approach using advanced technologies to:

1. Analyze human postmortem samples
2. Analyze human embryonic stem cells
3. Identify new metastable epialleles in humans
4. Elucidate new mechanisms and relationships between phenotypic variation and methylation variability

The combination of the algorithm to identify methylation variability and the use of stem cell models to functionally characterize epigenetic variants will serve as a blueprint for the analysis of the epigenetic contribution to other endocrine, neurological, or cardiovascular diseases. This will generate a powerful resource for researchers worldwide.