Epimutations in both the TESK2 and MMACHC promoters in the Epi-cblC inherited disorder of intracellular metabolism of vitamin B12

Springer Science and Business Media LLC - Tập 14 Số 1 - 2022
Abderrahim Oussalah1, Youssef Siblini1, Sébastien Hergalant1, Céline Chéry1, Pierre Rouyer1, Catia Cavicchi2, Renzo Guerrini2, Pierre‐Emmanuel Morange3, David‐Alexandre Trégouët4, Mihaela Pupavac5, David K. Watkins5, Tomi Pastinen5, Wendy K. Chung6, Can Fıçıcıoğlu7, François Feillet8, D. Sean Froese9, Matthias Baumgartner9, Jean‐François Benoist10, Jacek Majewski5, Amelia Morrone11, David S. Rosenblatt5, Jean Louis Guéant12
1INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy, University of Lorraine, 9 Avenue de la Forêt de Haye, 54000, Nancy, France
2Molecular and Cell Biology Laboratory of Neurometabolic Diseases, Paediatric Neurology Unit and Laboratories, Meyer Children’s Hospital, Viale Pieraccini 24, 50139, Florence, Italy
3INSERM UMR_S 1263, Center for CardioVascular and Nutrition Research (C2VN), Aix-Marseille University, 13385, Marseille, France
4INSERM, BPH, U1219, Université Bordeaux, 33000, Bordeaux, France
5Department of Human Genetics, McGill University and Research Institute, McGill University Health Centre, Montreal, QC, H4A 3J1, Canada
6Departments of Pediatrics and Medicine, Columbia University, New York, USA
7Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
8Reference Center for Inborn Errors of Metabolism (ORPHA67872), University Hospital of Nancy, 54000 Nancy, France
9Division of Metabolism, University Children’s Hospital, University of Zürich, Zürich, Switzerland
10Biochemistry Hormonology Laboratory, Robert-Debré University Hospital, APHP, 48 bd Serurier, 75019, Paris, France
11Department of NEUROFARBA, University of Florence, Florence, Italy
12Department of Molecular Medicine, Division of Biochemistry, Molecular Biology and Nutrition, University Hospital of Nancy, 54000, Nancy, France

Tóm tắt

AbstractBackgroundepi-cblCis a recently discovered inherited disorder of intracellular vitamin B12metabolism associating hematological, neurological, and cardiometabolic outcomes. It is produced by an epimutation at the promoter common toCCDC163PandMMACHC, which results from an aberrant antisense transcription due to splicing mutations in the antisensePRDX1gene neighboringMMACHC. We studied whether the aberrant transcription produced a second epimutation by encompassing the CpG island of theTESK2gene neighboringCCDC163P.MethodsWe unraveled the methylome architecture of theCCDC163P–MMACHCCpG island (CpG:33) and theTESK2CpG island (CpG:51) of 17 epi-cblCcases. We performed an integrative analysis of the DNA methylome profiling, transcriptome reconstruction of RNA-sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-Seq) of histone H3, and transcription expression ofMMACHCandTESK2.ResultsThePRDX1splice mutations and activation of numerous cryptic splice sites produced antisense readthrough transcripts encompassing the bidirectionalMMACHC/CCDC163Ppromoter and theTESK2promoter, resulting in the silencing of both theMMACHCandTESK2genes through the deposition of SETD2-dependent H3K36me3 marks and the generation of epimutations in the CpG islands of the two promoters.ConclusionsThe antisense readthrough transcription of the mutatedPRDX1produces an epigenetic silencing ofMMACHCandTESK2. We propose using the term 'epi-digenism' to define this epigenetic disorder that affects two genes. Epi-cblCis an entity that differs fromcblC.Indeed, thePRDX1 and TESK2altered expressions are observed in epi-cblCbut not incblC, suggesting further evaluating the potential consequences on cancer risk and spermatogenesis.

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