Integration and reanalysis of transcriptomics and methylomics data derived from blood and testis tissue of men with 47,XXY Klinefelter syndrome indicates the primary involvement of Sertoli cells in the testicular pathogenesis

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Integration and reanalysis of transcriptomics and methylomics data derived from blood and testis tissue of men with 47,XXY Klinefelter syndrome indicates the primary involvement of Sertoli cells in the testicular pathogenesis. / Winge, Sofia B.; Soraggi, Samuele; Schierup, Mikkel H.; Rajpert-De Meyts, Ewa; Almstrup, Kristian.

In: American Journal of Medical Genetics. Part C: Seminars in Medical Genetics, Vol. 184, No. 2, 06.2020, p. 239-255.

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Winge, Sofia B. ; Soraggi, Samuele ; Schierup, Mikkel H. ; Rajpert-De Meyts, Ewa ; Almstrup, Kristian. / Integration and reanalysis of transcriptomics and methylomics data derived from blood and testis tissue of men with 47,XXY Klinefelter syndrome indicates the primary involvement of Sertoli cells in the testicular pathogenesis. In: American Journal of Medical Genetics. Part C: Seminars in Medical Genetics. 2020 ; Vol. 184, No. 2. pp. 239-255.

Bibtex

@article{aac4fc0a35654f57b0862309582a3299,
title = "Integration and reanalysis of transcriptomics and methylomics data derived from blood and testis tissue of men with 47,XXY Klinefelter syndrome indicates the primary involvement of Sertoli cells in the testicular pathogenesis",
abstract = "Klinefelter syndrome (KS; 47,XXY) is the most common sex chromosomal anomaly and causes a multitude of symptoms. Often the most noticeable symptom is infertility caused by azoospermia with testicular histology showing hyalinization of tubules, germ cells loss, and Leydig cell hyperplasia. The germ cell loss begins early in life leading to partial hyalinization of the testis at puberty, but the mechanistic drivers behind this remain poorly understood. In this systematic review, we summarize the current knowledge on developmental changes in the cellularity of KS gonads supplemented by a comparative analysis of the fetal and adult gonadal transcriptome, and blood transcriptome and methylome of men with KS. We identified a high fraction of upregulated genes that escape X-chromosome inactivation, thus supporting previous hypotheses that these are the main drivers of the testicular phenotype in KS. Enrichment analysis showed overrepresentation of genes from the X- and Y-chromosome and testicular transcription factors. Furthermore, by re-evaluation of recent single cell RNA-sequencing data originating from adult KS testis, we found novel evidence that the Sertoli cell is the most affected cell type. Our results are consistent with disturbed cross-talk between somatic and germ cells in the KS testis, and with X-escapee genes acting as mediators.",
keywords = "human testis, Klinefelter syndrome, methylome, single cell RNA-sequencing, transcriptome, X-CHROMOSOME INACTIVATION, GERM-CELLS, SEX-CHROMOSOMES, EXPRESSION PATTERNS, CLINICAL PHENOTYPE, ANDROGEN RECEPTOR, GENE-EXPRESSION, NONCODING RNAS, MOUSE, BOYS",
author = "Winge, {Sofia B.} and Samuele Soraggi and Schierup, {Mikkel H.} and {Rajpert-De Meyts}, Ewa and Kristian Almstrup",
year = "2020",
month = jun,
doi = "10.1002/ajmg.c.31793",
language = "English",
volume = "184",
pages = "239--255",
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 - Integration and reanalysis of transcriptomics and methylomics data derived from blood and testis tissue of men with 47,XXY Klinefelter syndrome indicates the primary involvement of Sertoli cells in the testicular pathogenesis

AU - Winge, Sofia B.

AU - Soraggi, Samuele

AU - Schierup, Mikkel H.

AU - Rajpert-De Meyts, Ewa

AU - Almstrup, Kristian

PY - 2020/6

Y1 - 2020/6

N2 - Klinefelter syndrome (KS; 47,XXY) is the most common sex chromosomal anomaly and causes a multitude of symptoms. Often the most noticeable symptom is infertility caused by azoospermia with testicular histology showing hyalinization of tubules, germ cells loss, and Leydig cell hyperplasia. The germ cell loss begins early in life leading to partial hyalinization of the testis at puberty, but the mechanistic drivers behind this remain poorly understood. In this systematic review, we summarize the current knowledge on developmental changes in the cellularity of KS gonads supplemented by a comparative analysis of the fetal and adult gonadal transcriptome, and blood transcriptome and methylome of men with KS. We identified a high fraction of upregulated genes that escape X-chromosome inactivation, thus supporting previous hypotheses that these are the main drivers of the testicular phenotype in KS. Enrichment analysis showed overrepresentation of genes from the X- and Y-chromosome and testicular transcription factors. Furthermore, by re-evaluation of recent single cell RNA-sequencing data originating from adult KS testis, we found novel evidence that the Sertoli cell is the most affected cell type. Our results are consistent with disturbed cross-talk between somatic and germ cells in the KS testis, and with X-escapee genes acting as mediators.

AB - Klinefelter syndrome (KS; 47,XXY) is the most common sex chromosomal anomaly and causes a multitude of symptoms. Often the most noticeable symptom is infertility caused by azoospermia with testicular histology showing hyalinization of tubules, germ cells loss, and Leydig cell hyperplasia. The germ cell loss begins early in life leading to partial hyalinization of the testis at puberty, but the mechanistic drivers behind this remain poorly understood. In this systematic review, we summarize the current knowledge on developmental changes in the cellularity of KS gonads supplemented by a comparative analysis of the fetal and adult gonadal transcriptome, and blood transcriptome and methylome of men with KS. We identified a high fraction of upregulated genes that escape X-chromosome inactivation, thus supporting previous hypotheses that these are the main drivers of the testicular phenotype in KS. Enrichment analysis showed overrepresentation of genes from the X- and Y-chromosome and testicular transcription factors. Furthermore, by re-evaluation of recent single cell RNA-sequencing data originating from adult KS testis, we found novel evidence that the Sertoli cell is the most affected cell type. Our results are consistent with disturbed cross-talk between somatic and germ cells in the KS testis, and with X-escapee genes acting as mediators.

KW - human testis

KW - Klinefelter syndrome

KW - methylome

KW - single cell RNA-sequencing

KW - transcriptome

KW - X-CHROMOSOME INACTIVATION

KW - GERM-CELLS

KW - SEX-CHROMOSOMES

KW - EXPRESSION PATTERNS

KW - CLINICAL PHENOTYPE

KW - ANDROGEN RECEPTOR

KW - GENE-EXPRESSION

KW - NONCODING RNAS

KW - MOUSE

KW - BOYS

U2 - 10.1002/ajmg.c.31793

DO - 10.1002/ajmg.c.31793

M3 - Review

C2 - 32449318

VL - 184

SP - 239

EP - 255

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 -