Transcriptome analysis of the adult human Klinefelter testis and cellularity-matched controls reveals disturbed differentiation of Sertoli- and Leydig cells

Sofia Boeg Winge; Marlene Danner Dalgaard; Kirstine G Belling; Jacob Malte Jensen; John Erik Nielsen; Lise Aksglaede; Mikkel Heide Schierup; Søren Brunak; Niels Erik Skakkebæk; Anders Juul; Ewa Rajpert-De Meyts; Kristian Almstrup

doi:10.1038/s41419-018-0671-1

Transcriptome analysis of the adult human Klinefelter testis and cellularity-matched controls reveals disturbed differentiation of Sertoli- and Leydig cells

Sofia Boeg Winge, Marlene Danner Dalgaard, Kirstine G Belling, Jacob Malte Jensen, John Erik Nielsen, Lise Aksglaede, Mikkel Heide Schierup, Søren Brunak, Niels Erik Skakkebæk, Anders Juul, Ewa Rajpert-De Meyts, Kristian Almstrup

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Abstract

The most common human sex chromosomal disorder is Klinefelter syndrome (KS; 47,XXY). Adult patients with KS display a diverse phenotype but are nearly always infertile, due to testicular degeneration at puberty. To identify mechanisms causing the selective destruction of the seminiferous epithelium, we performed RNA-sequencing of 24 fixed paraffin-embedded testicular tissue samples. Analysis of informative transcriptomes revealed 235 differentially expressed transcripts (DETs) in the adult KS testis showing enrichment of long non-coding RNAs, but surprisingly not of X-chromosomal transcripts. Comparison to 46,XY samples with complete spermatogenesis and Sertoli cell-only-syndrome allowed prediction of the cellular origin of 71 of the DETs. DACH2 and FAM9A were validated by immunohistochemistry and found to mark apparently undifferentiated somatic cell populations in the KS testes. Moreover, transcriptomes from fetal, pre-pubertal, and adult KS testes showed a limited overlap, indicating that different mechanisms are likely to operate at each developmental stage. Based on our data, we propose that testicular degeneration in men with KS is a consequence of germ cells loss initiated during early development in combination with disturbed maturation of Sertoli- and Leydig cells.

Original language	English
Article number	586
Journal	Cell Death & Disease
Volume	9
Issue number	6
Number of pages	14
ISSN	2041-4889
DOIs	https://doi.org/10.1038/s41419-018-0671-1
Publication status	Published - 1 Jun 2018

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Transcriptome analysis of the adult human Klinefelter testis and cellularity-matched controls reveals disturbed differentiation of Sertoli- and Leydig cellsFinal published version, 2.97 MB

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Winge, S. B., Dalgaard, M. D., Belling, K. G., Jensen, J. M., Nielsen, J. E., Aksglaede, L., Schierup, M. H., Brunak, S., Skakkebæk, N. E., Juul, A., Rajpert-De Meyts, E., & Almstrup, K. (2018). Transcriptome analysis of the adult human Klinefelter testis and cellularity-matched controls reveals disturbed differentiation of Sertoli- and Leydig cells. Cell Death & Disease, 9(6), [586]. https://doi.org/10.1038/s41419-018-0671-1

Transcriptome analysis of the adult human Klinefelter testis and cellularity-matched controls reveals disturbed differentiation of Sertoli- and Leydig cells. / Winge, Sofia Boeg; Dalgaard, Marlene Danner; Belling, Kirstine G et al.

In: Cell Death & Disease, Vol. 9, No. 6, 586, 01.06.2018.

Research output: Contribution to journal › Journal article › Research › peer-review

Winge, SB, Dalgaard, MD, Belling, KG, Jensen, JM, Nielsen, JE, Aksglaede, L, Schierup, MH, Brunak, S , Skakkebæk, NE , Juul, A, Rajpert-De Meyts, E & Almstrup, K 2018, 'Transcriptome analysis of the adult human Klinefelter testis and cellularity-matched controls reveals disturbed differentiation of Sertoli- and Leydig cells', Cell Death & Disease, vol. 9, no. 6, 586. https://doi.org/10.1038/s41419-018-0671-1

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title = "Transcriptome analysis of the adult human Klinefelter testis and cellularity-matched controls reveals disturbed differentiation of Sertoli- and Leydig cells",

abstract = "The most common human sex chromosomal disorder is Klinefelter syndrome (KS; 47,XXY). Adult patients with KS display a diverse phenotype but are nearly always infertile, due to testicular degeneration at puberty. To identify mechanisms causing the selective destruction of the seminiferous epithelium, we performed RNA-sequencing of 24 fixed paraffin-embedded testicular tissue samples. Analysis of informative transcriptomes revealed 235 differentially expressed transcripts (DETs) in the adult KS testis showing enrichment of long non-coding RNAs, but surprisingly not of X-chromosomal transcripts. Comparison to 46,XY samples with complete spermatogenesis and Sertoli cell-only-syndrome allowed prediction of the cellular origin of 71 of the DETs. DACH2 and FAM9A were validated by immunohistochemistry and found to mark apparently undifferentiated somatic cell populations in the KS testes. Moreover, transcriptomes from fetal, pre-pubertal, and adult KS testes showed a limited overlap, indicating that different mechanisms are likely to operate at each developmental stage. Based on our data, we propose that testicular degeneration in men with KS is a consequence of germ cells loss initiated during early development in combination with disturbed maturation of Sertoli- and Leydig cells.",

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AU - Winge, Sofia Boeg

AU - Dalgaard, Marlene Danner

AU - Belling, Kirstine G

AU - Jensen, Jacob Malte

AU - Nielsen, John Erik

AU - Aksglaede, Lise

AU - Schierup, Mikkel Heide

AU - Brunak, Søren

AU - Skakkebæk, Niels Erik

AU - Juul, Anders

AU - Rajpert-De Meyts, Ewa

AU - Almstrup, Kristian

PY - 2018/6/1

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N2 - The most common human sex chromosomal disorder is Klinefelter syndrome (KS; 47,XXY). Adult patients with KS display a diverse phenotype but are nearly always infertile, due to testicular degeneration at puberty. To identify mechanisms causing the selective destruction of the seminiferous epithelium, we performed RNA-sequencing of 24 fixed paraffin-embedded testicular tissue samples. Analysis of informative transcriptomes revealed 235 differentially expressed transcripts (DETs) in the adult KS testis showing enrichment of long non-coding RNAs, but surprisingly not of X-chromosomal transcripts. Comparison to 46,XY samples with complete spermatogenesis and Sertoli cell-only-syndrome allowed prediction of the cellular origin of 71 of the DETs. DACH2 and FAM9A were validated by immunohistochemistry and found to mark apparently undifferentiated somatic cell populations in the KS testes. Moreover, transcriptomes from fetal, pre-pubertal, and adult KS testes showed a limited overlap, indicating that different mechanisms are likely to operate at each developmental stage. Based on our data, we propose that testicular degeneration in men with KS is a consequence of germ cells loss initiated during early development in combination with disturbed maturation of Sertoli- and Leydig cells.

AB - The most common human sex chromosomal disorder is Klinefelter syndrome (KS; 47,XXY). Adult patients with KS display a diverse phenotype but are nearly always infertile, due to testicular degeneration at puberty. To identify mechanisms causing the selective destruction of the seminiferous epithelium, we performed RNA-sequencing of 24 fixed paraffin-embedded testicular tissue samples. Analysis of informative transcriptomes revealed 235 differentially expressed transcripts (DETs) in the adult KS testis showing enrichment of long non-coding RNAs, but surprisingly not of X-chromosomal transcripts. Comparison to 46,XY samples with complete spermatogenesis and Sertoli cell-only-syndrome allowed prediction of the cellular origin of 71 of the DETs. DACH2 and FAM9A were validated by immunohistochemistry and found to mark apparently undifferentiated somatic cell populations in the KS testes. Moreover, transcriptomes from fetal, pre-pubertal, and adult KS testes showed a limited overlap, indicating that different mechanisms are likely to operate at each developmental stage. Based on our data, we propose that testicular degeneration in men with KS is a consequence of germ cells loss initiated during early development in combination with disturbed maturation of Sertoli- and Leydig cells.

U2 - 10.1038/s41419-018-0671-1

DO - 10.1038/s41419-018-0671-1

M3 - Journal article

C2 - 29789566

SN - 2041-4889

VL - 9

JO - Cell Death & Disease

JF - Cell Death & Disease

IS - 6

M1 - 586

ER -

Transcriptome analysis of the adult human Klinefelter testis and cellularity-matched controls reveals disturbed differentiation of Sertoli- and Leydig cells

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