1CM

The early deficiency in methyl donor micronutrients increases the risk of birth defects and can alter brain development and produce fetal programming mechanisms with potential lifelong effects on complex metabolic diseases. This results from complex mechanisms in which the interplay between genetics, epigenomics and metabolic and nutritional factors of the one carbon metabolism (1-CM) is suspected to have a prominent role. The team will dissect this crosstalk to investigate pathogenesis of neurodevelopmental diseases, inborn errors of Cbl metabolism and complex diseases related to foetal programming, using mice, rats and fibroblasts and cohort studies.

The project is developed in 3 tasks:

1. In the « one-carbon metabolism and neurodevelopment » task, we will dissect the mechanisms of altered hippocampal plasticity of our transgenic/nutritional animal models and the genetic/epigenomics interplay in patient files with neurodevelopmental disorders.
   
   
2. In the task on “pathomechanisms of inherited diseases of the one carbon metabolism”, we will study the consequences of mutations on the partitioning of intracellular Cbl processing and the molecular consequences of inborn errors of Cbl metabolism through epigenomic mechanisms and inadequate responses to cellular stress.
   
   
3. The third task will evaluate the influence of methyl donors and the 1-CM on “developmental origins of complex diseases”. We will study the consequences of impaired 1-CM on the fetal development of brain, liver and heart and the transgenerational inheritance of the epigenomic alterations in our transgenic/nutritional animal models. We will rely on cohorts hosted in the FHU project ARRIMAGE and replicate our results in cohorts from our national and international collaborations. We aim to characterize epigenome/genome/metabolic signatures at birth that result from impaired 1-CM and influence gene expression and determinants of metabolic syndrome components during the first 5-8 years of life. We will identify tissue signatures that predict NASH and cardiomyopathy in our ALDEPI cohort of patients operated for severe obesity and will assess whether some of signatures identified in the early challenge are similar to those that predict outcomes of adult patients and vice versa.