EpiGenOmics/genomic/metabolic interplay in pathomechanisms of iNborn Errors of methionine metabolism. – EpiGONE

The cblC type of rare disease of vitamin B12 metabolism due to mutations in the MMACHC gene is a severe and sometimes fatal disease with metabolic decompensation, megaloblastic anemia, retinopathy, neurological disorders. We have discovered a new type of cblC called epi-cblC produced by an epimutation on MMACHC, which is present in 3 generations and in the sperm/germ cells of fathers of probants. MMACHC is a sense gene surrounded by CCDC163P and PRDX1 oriented in opposite directions. A mutation in PRDX1 produces an aberrant antisense transcription encompassing the bidirectional CCDC163P / MMACHC promoter, which is responsible for an H3K36me3 histone mark and the epimutation. We identified 20 epi-cblC cases including 11 neonatal screening (10% of cases classified cblC). Two cases have been published in China, including one without a PRDX1 mutation. PRDX1 transcription is high in spermatogonia but undetectable in spermatids. The epimutation could therefore be secondarily maintained in spermatids and differentiated cells independent of aberrant PRDX1 transcription. The aim of EpiGONE is to decipher the mechanisms that generate the epimutation and its maintenance in germ cells and somatic cells. The project includes 4 work packages (WP): WP1, preparation of cell models; WP2, genesis of epimutation, study of the role of DNMT3B1, histone mark H3K36me3 and SETD2, maintenance of the epimutation after abolished aberrant transcription in cells modified by CrispR / Cas9, influence of cellular stress; WP3, study of the maintenance and generational transmission of the epimutation in epi-cblC mice; WP4: Evaluation of treatments to erase the epimutation by targeting DNMT or SETD2 in cells of epi-cblC patients and mice.
EpiGONE will help to elucidate the mechanism of generation and maintenance of epimutations using epi-cblC as a model and will provide a perspective for treating severe cases of epi-cblC.