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

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 article

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^*

^*Corresponding author for this work

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

345 Downloads (Pure)

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	671
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

Bibliographical note

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any mediumor format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if
changesweremade. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Access to Document

10.1038/s41419-018-0671-1

Winge et al 2018Final published version, 2.97 MB

OpenUrl availability

Full text

Cite this

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 article. Cell Death & Disease, 9(6), [671]. https://doi.org/10.1038/s41419-018-0671-1

@article{381667e08a344b93aee6b8ea60d71b1f,

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

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.",

author = "Winge, {Sofia Boeg} and Dalgaard, {Marlene Danner} and Belling, {Kirstine G.} and Jensen, {Jacob Malte} and Nielsen, {John Erik} and Lise Aksglaede and Schierup, {Mikkel Heide} and S{\o}ren Brunak and Skakkeb{\ae}k, {Niels Erik} and Anders Juul and {Rajpert-De Meyts}, Ewa and Kristian Almstrup",

note = "This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any mediumor format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changesweremade. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article{\textquoteright}s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.",

year = "2018",

month = jun,

day = "1",

doi = "10.1038/s41419-018-0671-1",

language = "English",

volume = "9",

journal = "Cell Death and Disease",

issn = "2041-4889",

publisher = "Nature Publishing Group",

number = "6",

}

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 article', Cell Death & Disease, vol. 9, no. 6, 671. 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 article. / Winge, Sofia Boeg; Dalgaard, Marlene Danner; Belling, Kirstine G. et al.
In: Cell Death & Disease, Vol. 9, No. 6, 671, 01.06.2018.

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

TY - JOUR

T1 - Transcriptome analysis of the adult human Klinefelter testis and cellularity-matched controls reveals disturbed differentiation of Sertoli- and Leydig cells article

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

N1 - This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any mediumor format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changesweremade. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

PY - 2018/6/1

Y1 - 2018/6/1

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

AN - SCOPUS:85047620969

SN - 2041-4889

VL - 9

JO - Cell Death and Disease

JF - Cell Death and Disease

IS - 6

M1 - 671

ER -

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

Abstract

Bibliographical note

Access to Document

OpenUrl availability

Fingerprint

Cite this