One-Carbon Metabolism (1-CM) and the Epigenomic Basis of the Developmental Origins of Inherited and Complex Diseases
Leader: Prof. Rosa-Maria GUEANT-RODRIGUEZ
Co-leader: Dr David COELHO
Early deficiency in methyl donor micronutrients increases the risk of congenital malformations and may impair brain development while inducing fetal programming mechanisms that can have lifelong consequences for complex metabolic diseases. These effects result from intricate biological mechanisms in which interactions among genetics, epigenomics, and metabolic and nutritional factors involved in one-carbon metabolism (1-CM) are believed to play a central role.
The team investigates this complex interplay to better understand the pathogenesis of neurodevelopmental disorders, inherited disorders of cobalamin (vitamin B12) metabolism, and complex diseases associated with fetal programming. Research is conducted using mouse and rat models, fibroblast-based studies, and human cohort investigations.
The 3 Research Areas of the Team
Group 1: Abnormal Brain Development and Aging: Environmental, Nutritional, Metabolic, and Epigenomic Interactions
Lead: Prof. Carine BOSSENMEYER-POURIE
Within this research area, we investigate the mechanisms underlying impaired hippocampal plasticity in our transgenic and nutritional animal models, as well as the genetic and epigenomic interactions involved in neurodevelopmental disorders in patients. Our research aims to decipher how environmental, nutritional, metabolic, and epigenomic factors contribute to abnormal brain development and aging processes.
Group 2: Pathophysiological Mechanisms and Personalized Treatments in Rare Metabolic Disorders
Lead: Dr David COELHO
Within this research area, we investigate the consequences of genetic mutations on the intracellular compartmentalization of cobalamin (vitamin B12) metabolism, as well as the molecular mechanisms underlying inherited disorders of cobalamin metabolism. Particular emphasis is placed on epigenomic alterations and maladaptive cellular stress responses that contribute to disease pathophysiology. Our objective is to improve the understanding of these rare metabolic disorders and to support the development of personalized therapeutic strategies.
Group 3: Fetal Programming and Life-Course Trajectories in Obesity-Related Complex Metabolic Diseases
Lead: Prof. Rosa-Maria GUEANT-RODRIGUEZ
Within this research area, we investigate the consequences of disrupted one-carbon metabolism (1-CM) on the fetal development of the brain, liver, and heart, as well as on the transgenerational transmission of epigenomic alterations in our transgenic and nutritional animal models. Our studies rely on the cohorts hosted within the FHU ARRIMAGE project and are further validated in cohorts derived from our national and international collaborations.
Our objective is to characterize the epigenomic, genomic, and metabolic signatures present at birth that result from altered 1-CM and influence gene expression as well as the determinants of metabolic syndrome components during the first five to eight years of life. We also identify tissue signatures predictive of non-alcoholic steatohepatitis (NASH) and cardiomyopathy in our ALDEPI cohort of patients who have undergone bariatric surgery for severe obesity. Furthermore, we assess whether some of the signatures identified in adults are shared with those predicting early-life outcomes, and conversely whether neonatal signatures can predict health trajectories later in life.
