Iver Kristiansen Nordentoft

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

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Epigenetic and transcriptomic consequences of excess X-chromosome material in 47,XXX syndrome-A comparison with Turner syndrome and 46,XX females. / Nielsen, Morten Muhlig; Trolle, Christian; Vang, Søren; Hornshøj, Henrik; Skakkebaek, Anne; Hedegaard, Jakob; Nordentoft, Iver; Pedersen, Jakob Skou; Gravholt, Claus Højbjerg.

In: American Journal of Medical Genetics. Part C: Seminars in Medical Genetics, Vol. 184, No. 2, 06.2020, p. 279-293.

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@article{6205030a4daa4307b437dc399dcbd094,
title = "Epigenetic and transcriptomic consequences of excess X-chromosome material in 47,XXX syndrome-A comparison with Turner syndrome and 46,XX females",
abstract = "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.",
keywords = "BIOCONDUCTOR PACKAGE, DIFFERENTIAL EXPRESSION ANALYSIS, DNA METHYLATION, DNA-methylation, GENE, INACTIVATION, KLINEFELTER SYNDROME, PHENOTYPE, PROTEIN, TRISOMY X, Turner syndrome, WOMEN, X chromosome inactivation, X-chromosome aneuploidies, differential gene expression, triple-X",
author = "Nielsen, {Morten Muhlig} and Christian Trolle and S{\o}ren Vang and Henrik Hornsh{\o}j and Anne Skakkebaek and Jakob Hedegaard and Iver Nordentoft and Pedersen, {Jakob Skou} and Gravholt, {Claus H{\o}jbjerg}",
note = "{\textcopyright} 2020 Wiley Periodicals LLC.",
year = "2020",
month = jun,
doi = "10.1002/ajmg.c.31799",
language = "English",
volume = "184",
pages = "279--293",
journal = "American Journal of Medical Genetics. Part C: Seminars in Medical Genetics",
issn = "1552-4868",
publisher = "JohnWiley & Sons, Inc.",
number = "2",

}

RIS

TY - JOUR

T1 - Epigenetic and transcriptomic consequences of excess X-chromosome material in 47,XXX syndrome-A comparison with Turner syndrome and 46,XX females

AU - Nielsen, Morten Muhlig

AU - Trolle, Christian

AU - Vang, Søren

AU - Hornshøj, Henrik

AU - Skakkebaek, Anne

AU - Hedegaard, Jakob

AU - Nordentoft, Iver

AU - Pedersen, Jakob Skou

AU - Gravholt, Claus Højbjerg

N1 - © 2020 Wiley Periodicals LLC.

PY - 2020/6

Y1 - 2020/6

N2 - 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.

AB - 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.

KW - BIOCONDUCTOR PACKAGE

KW - DIFFERENTIAL EXPRESSION ANALYSIS

KW - DNA METHYLATION

KW - DNA-methylation

KW - GENE

KW - INACTIVATION

KW - KLINEFELTER SYNDROME

KW - PHENOTYPE

KW - PROTEIN

KW - TRISOMY X

KW - Turner syndrome

KW - WOMEN

KW - X chromosome inactivation

KW - X-chromosome aneuploidies

KW - differential gene expression

KW - triple-X

U2 - 10.1002/ajmg.c.31799

DO - 10.1002/ajmg.c.31799

M3 - Journal article

C2 - 32489015

VL - 184

SP - 279

EP - 293

JO - American Journal of Medical Genetics. Part C: Seminars in Medical Genetics

JF - American Journal of Medical Genetics. Part C: Seminars in Medical Genetics

SN - 1552-4868

IS - 2

ER -