TY - JOUR
T1 - Comparative single-cell analysis of biopsies clarifies pathogenic mechanisms in Klinefelter syndrome
AU - Mahyari, Eisa
AU - Guo, Jingtao
AU - Lima, Ana C.
AU - Lewinsohn, Daniel P.
AU - Stendahl, Alexandra M.
AU - Vigh-Conrad, Katinka A.
AU - Nie, Xichen
AU - Nagirnaja, Liina
AU - Rockweiler, Nicole B.
AU - Carrell, Douglas T.
AU - Hotaling, James M.
AU - Aston, Kenneth I.
AU - Conrad, Donald F.
N1 - Publisher Copyright:
© 2021 American Society of Human Genetics
PY - 2021/10/7
Y1 - 2021/10/7
N2 - Klinefelter syndrome (KS), also known as 47, XXY, is characterized by a distinct set of physiological abnormalities, commonly including infertility. The molecular basis for Klinefelter-related infertility is still unclear, largely because of the cellular complexity of the testis and the intricate endocrine and paracrine signaling that regulates spermatogenesis. Here, we demonstrate an analysis framework for dissecting human testis pathology that uses comparative analysis of single-cell RNA-sequencing data from the biopsies of 12 human donors. By comparing donors from a range of ages and forms of infertility, we generate gene expression signatures that characterize normal testicular function and distinguish clinically distinct forms of male infertility. Unexpectedly, we identified a subpopulation of Sertoli cells within multiple individuals with KS that lack transcription from the XIST locus, and the consequence of this is increased X-linked gene expression compared to all other KS cell populations. By systematic assessment of known cell signaling pathways, we identify 72 pathways potentially active in testis, dozens of which appear upregulated in KS. Altogether our data support a model of pathogenic changes in interstitial cells cascading from loss of X inactivation in pubertal Sertoli cells and nominate dosage-sensitive factors secreted by Sertoli cells that may contribute to the process. Our findings demonstrate the value of comparative patient analysis in mapping genetic mechanisms of disease and identify an epigenetic phenomenon in KS Sertoli cells that may prove important for understanding causes of infertility and sex chromosome evolution.
AB - Klinefelter syndrome (KS), also known as 47, XXY, is characterized by a distinct set of physiological abnormalities, commonly including infertility. The molecular basis for Klinefelter-related infertility is still unclear, largely because of the cellular complexity of the testis and the intricate endocrine and paracrine signaling that regulates spermatogenesis. Here, we demonstrate an analysis framework for dissecting human testis pathology that uses comparative analysis of single-cell RNA-sequencing data from the biopsies of 12 human donors. By comparing donors from a range of ages and forms of infertility, we generate gene expression signatures that characterize normal testicular function and distinguish clinically distinct forms of male infertility. Unexpectedly, we identified a subpopulation of Sertoli cells within multiple individuals with KS that lack transcription from the XIST locus, and the consequence of this is increased X-linked gene expression compared to all other KS cell populations. By systematic assessment of known cell signaling pathways, we identify 72 pathways potentially active in testis, dozens of which appear upregulated in KS. Altogether our data support a model of pathogenic changes in interstitial cells cascading from loss of X inactivation in pubertal Sertoli cells and nominate dosage-sensitive factors secreted by Sertoli cells that may contribute to the process. Our findings demonstrate the value of comparative patient analysis in mapping genetic mechanisms of disease and identify an epigenetic phenomenon in KS Sertoli cells that may prove important for understanding causes of infertility and sex chromosome evolution.
KW - Klinefelter syndrome
KW - Leydig cells
KW - SDA
KW - Sertoli cells
KW - X chromosome inactivation
KW - azoospermia
KW - male infertility
KW - matrix factorization
KW - single-cell sequencing
KW - testis
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U2 - 10.1016/j.ajhg.2021.09.001
DO - 10.1016/j.ajhg.2021.09.001
M3 - Article
C2 - 34626582
AN - SCOPUS:85116913246
SN - 0002-9297
VL - 108
SP - 1924
EP - 1945
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 10
ER -