A KHDC3L mutation resulting in recurrent hydatidiform mole causes genome-wide DNA methylation loss in oocytes and persistent imprinting defects post-fertilisation

Genome Medicine

Simon Andrews¹  Maryam Davari²  Mojgan Akbarzadeh Jahromi³  Angela Sparago⁴  Hannah Demond⁵  Gavin Kelsey⁵  David Monk⁶  Zahra Anvar⁷  Bahia Namavar Jahromi⁷  Andrea Riccio⁸  Ankit Verma⁸  Silvia Russo⁹  Luciano Calzari⁹ 

[1] Bioinformatics Group, Babraham Institute;Department of Obstetrics and Gynecology, School of Medicine, Shiraz University of Medical Sciences;Department of Pathology, Shiraz University of Medical Sciences;Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, Università degli Studi della Campania ‘Luigi Vanvitelli’;Epigenetics Programme, Babraham Institute;Imprinting and Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat;Infertility Research Center, Shiraz University of Medical Sciences;Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, Consiglio Nazionale delle Ricerche (CNR);Medical Cytogenetics and Molecular Genetics Laboratory, Centro di Ricerche e Tecnologie Biomediche IRCCS, Istituto Auxologico Italiano;

关键词: Epigenetics;    DNA methylation;    Genomic imprinting;    Single-cell analysis;    Oocytes;    Embryos;   

DOI  :  10.1186/s13073-019-0694-y

来源: DOAJ

【 摘 要 】

Abstract Background Maternal effect mutations in the components of the subcortical maternal complex (SCMC) of the human oocyte can cause early embryonic failure, gestational abnormalities and recurrent pregnancy loss. Enigmatically, they are also associated with DNA methylation abnormalities at imprinted genes in conceptuses: in the devastating gestational abnormality biparental complete hydatidiform mole (BiCHM) or in multi-locus imprinting disease (MLID). However, the developmental timing, genomic extent and mechanistic basis of these imprinting defects are unknown. The rarity of these disorders and the possibility that methylation defects originate in oocytes have made these questions very challenging to address. Methods Single-cell bisulphite sequencing (scBS-seq) was used to assess methylation in oocytes from a patient with BiCHM identified to be homozygous for an inactivating mutation in the human SCMC component KHDC3L. Genome-wide methylation analysis of a preimplantation embryo and molar tissue from the same patient was also performed. Results High-coverage scBS-seq libraries were obtained from five KHDC3L c.1A>G oocytes, which revealed a genome-wide deficit of DNA methylation compared with normal human oocytes. Importantly, germline differentially methylated regions (gDMRs) of imprinted genes were affected similarly to other sequence features that normally become methylated in oocytes, indicating no selectivity towards imprinted genes. A range of methylation losses was observed across genomic features, including gDMRs, indicating variable sensitivity to defects in the SCMC. Genome-wide analysis of a pre-implantation embryo and molar tissue from the same patient showed that following fertilisation methylation defects at imprinted genes persist, while most non-imprinted regions of the genome recover near-normal methylation post-implantation. Conclusions We show for the first time that the integrity of the SCMC is essential for de novo methylation in the female germline. These findings have important implications for understanding the role of the SCMC in DNA methylation and for the origin of imprinting defects, for counselling affected families, and will help inform future therapeutic approaches.

【 授权许可】

Unknown