Human metastable epialleles and their influence on disease susceptibility

• Applicant: Nady El Hajj, Ph.D.
• Subject Area: Human Genetics ; Developmental Biology ; Reproductive Medicine, Urology
• Term: from 2017 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 350775982

Metastable epialleles (MEs) are genomic regions that are variably expressed due to a variation in epigenetic regulation between individuals. DNA methylation at MEs is either established stochastically prior to gastrulation or inherited through the germline. This mechanism leads to inter-individual epigenetic variation that occurs systemically across all somatic tissues. DNA methylation changes at MEs can influence the phenotype as evident in the agouti viable yellow (Avy) mouse. DNA methylation at the Avy locus controls the expression of the agouti gene which is known to cause changes in fur color along with hyperphagic obesity during later adult life. Variable methylation at the POMC metastable epiallele was recently reported to be strongly associated with obesity. Notably, the establishment of epigenetic marks at MEs was shown to be modulated by the periconceptional environment. In this project, we aim to screen for human MEs via whole genome bisulfite sequencing across several tissues collected as part of the NIH Genotype-Tissue Expression (GTEx) program. We will identify whether DNA methylation variation at MEs is associated with genetic variants in cis and whether it regulates tissue-specific gene expression. Furthermore, we intend to determine whether methylation at MEs is epigenetically inherited through the germline or established stochastically during early embryonic development. Next, we plan to test if methylation at MEs can predict subsequent weight gain in a unique cohort of gainers (BMI increase > 4.5 kg/m2) and non-gainers (BMI increase < 1.3 kg/m2) recruited as part of the Starr County Health Studies. Finally, we will determine whether a diabetic intrauterine environment can have an effect on methylation establishment at MEs. The aims of this project are to 1) identify the majority of human MEs which would be of great value for future studies and 2) to determine whether epigenetic variation at MEs can predict obesity in later adult life

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Robert Waterland, Ph.D.