Epigenetic and transcriptomic consequences of excess X‐chromosome material in 47,XXX syndrome—A comparison with Turner syndrome and 46,XX females

• Published in: American journal of medical genetics. Part C, Seminars in medical genetics Vol. 184; no. 2; pp. 279 - 293
• Main Authors: Nielsen, Morten Muhlig, Trolle, Christian, Vang, Søren, Hornshøj, Henrik, Skakkebæk, Anne, Hedegaard, Jakob, Nordentoft, Iver, Pedersen, Jakob Skou, Gravholt, Claus Højbjerg
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-06-2020; Wiley Subscription Services, Inc
• Subjects: Abnormalities; Cell Cycle Proteins - genetics; Chromosomes; Chromosomes, Human, X - genetics; Deactivation; Demethylation; Deoxyribonucleic acid; differential gene expression; DNA; DNA methylation; DNA Methylation - genetics; Epigenesis, Genetic - genetics; Female; Females; Gene dosage; Gene Dosage - genetics; Gene expression; Gene Expression Regulation - genetics; Genes; Genes, X-Linked - genetics; Genetic disorders; Genetics; Genomes; Humans; Inactivation; Intercellular Signaling Peptides and Proteins - genetics; Interleukin 1; Interleukin-1 Receptor Accessory Protein - genetics; Leukocytes; Male; Microfilament Proteins - genetics; Morbidity; Receptor, Serotonin, 5-HT2C - genetics; Ribonucleic acid; RNA; Sex Chromosome Aberrations; Sex Chromosome Disorders of Sex Development - genetics; Sex Chromosome Disorders of Sex Development - pathology; Stoichiometry; Supernumerary; Transcriptome - genetics; triple‐X; Trisomy - genetics; Trisomy - pathology; Turner syndrome; Turner Syndrome - genetics; Turner Syndrome - pathology; Turner's syndrome; Women; X chromosome inactivation; X Chromosome Inactivation - genetics; X chromosomes; X‐chromosome aneuploidies; triple-X; differential gene expression; DNA-methylation; Turner syndrome; X chromosome inactivation; X-chromosome aneuploidies
• DOI: 10.1002/ajmg.c.31799
• EISSN: 1552-4876
• ISSN: 1552-4868

47,XXX (triple X) and Turner syndrome (45,X) are sex chromosomal abnormalities with detrimental effects on health with increased mortality and morbidity. In karyotypical normal females, X‐chromosome inactivation balances gene expression between sexes and upregulation of the X chromosome in both sexes maintain stoichiometry with the autosomes. In 47,XXX and Turner syndrome a gene dosage imbalance may ensue from increased or decreased expression from the genes that escape X inactivation, as well as from incomplete X chromosome inactivation in 47,XXX. We aim to study genome‐wide DNA‐methylation and RNA‐expression changes can explain phenotypic traits in 47,XXX syndrome. We compare DNA‐methylation and RNA‐expression data derived from white blood cells of seven women with 47,XXX syndrome, with data from seven female controls, as well as with seven women with Turner syndrome (45,X). To address these questions, we explored genome‐wide DNA‐methylation and transcriptome data in blood from seven females with 47,XXX syndrome, seven females with Turner syndrome, and seven karyotypically normal females (46,XX). Based on promoter methylation, we describe a demethylation of six X‐chromosomal genes (AMOT, HTR2C, IL1RAPL2, STAG2, TCEANC, ZNF673), increased methylation for GEMIN8, and four differentially methylated autosomal regions related to four genes (SPEG, MUC4, SP6, and ZNF492). We illustrate how these changes seem compensated at the transcriptome level although several genes show differential exon usage. In conclusion, our results suggest an impact of the supernumerary X chromosome in 47,XXX syndrome on the methylation status of selected genes despite an overall comparable expression profile.