Team 1

 

 

The one carbon metabolism and epigenomics in the developmental origins of inherited and complex diseases

 

 

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:

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.

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.

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.

 

 

Selected publications:

  1. Moreno-Garcia M, Guéant-Rodriguez RM, Pooya S, Brachet P, Alberto JM, Jeannesson E, Mskali F, Gueguen N, Marie PY, Lacolley P, Hermann MA, Juilliere Y, Malthiery Y, Guéant JL. Methyl donor deficiency produces a cardiomyopathy related to imbalanced methylation/acetylation of PGC-1a by PRMT1 and SIRT1 in the rat. J. Pathol., 2011, 225, 324-335 (IF 7.9)
  2. Pooya S, Blaise S, Moreno-Garcia M, Giudicelli J, Alberto JM, Guéant-Rodriguez RM, Jeannesson E, Gueguen N, Bressenot A, Nicolas B, Malthiery Y, Daval JL, Peyrin-Biroulet L, Bronowici JP, Guéant JL. Methyl donor deficiency impairs fatty acid oxidation through PGC-1α hypomehtylation and decreased ER-α, ERR-a and HNF-4α in the rat liver. J. Hepatol., 2012, 57, 344-351 (IF 10.6)
  3. Guéant JL, Namour F, Guéant-Rodriguez RM, Daval JL. Folate and fetal programming: a play in epigenomics ? Trends Endocrinol. Metab., 2013, 24, 279-289 (IF 9.0)
  4. Fofou-Caillierez MB, Mrabet NT, Chery C, Dreumont N, Flayac J, Pupavac M, Paoli J, Alberto JM, Coelho D, Camadro JM, Feillet F, Watkins D, Fowler B, Rosenblatt DS, Guéant JL. Interaction between methionine synthase isoforms and MMACHC: characterization in cblG-variant, cblG and cblC inherited causes of megaloblastic anaemia. Hum. Mol. Genet., 2013, 15, 4591-4601 (IF 6.0)
  5. Melhem H, Hansmannel F, Bressenot A, Battaglia-Hsu SF, Billioud V, Alberto JM, Gueant JL*, Peyrin-Biroulet L*. Methyl-deficient diet promotes colitis and SIRT1-mediated endoplasmic reticulum stress. Gut, 2016, 65, 595-606 (IF 14.9)
  6. Geoffroy  A, Kerek R, Pourié G, Helle D, Guéant JL, Daval JL, Bossenmeyer-Pourié C. Late maternal folate supplementation rescues from methyl donor deficiency-associated brain defects by restoring Let-7 and miT-34 pathways. Mol. Neurobiol., 2016, Aug 17 [Epub ahead of print] (IF 5.4)
  7. Coelho D*, Kim JC*, Miousse IR, Fung S, du Moulin M, Buers I, Suormala T, Burda P, Frapolli M, Stucki M, Nürnberg P, Thiele H, Robenek H, Höhne W, Longo N, Pasquali M, Mengel E, Watkins D, Shoubridge EA, Majewski J, Rosenblatt DS, Fowler B, Rutsch F, Baumgartner MR. Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism. Nature Genetics, 2012, 44, 1152-1155