Testicular expression of long non\u2013coding RNAs is affected by curative GnRHa treatment of cryptorchidism

Faruk Hadziselimovic,Beata Vincel,Michael B Stadler,Gilvydas Verkauskas

doi:10.1186/s12610-019-0097-3

Abstract

BackgroundCryptorchidism is a frequent endocrinopathy in boys that has been associated with an increased risk of developing testicular cancer and infertility. The condition is curable by combined surgery and hormonal treatment during early pre-pubertal stages using gonadotropin releasing hormone agonist (GnRHa). However, whether the treatment also alters the expression of testicular long non-coding RNAs (lncRNAs) is unknown. To gain insight into the effect of GnRHa on testicular lncRNA levels, we re-analyzed an expression dataset generated from testicular biopsies obtained during orchidopexy for bilateral cryptorchidism.ResultsWe identified EGFR-AS1, Linc-ROR, LINC00221, LINC00261, LINC00282, LINC00293, LINC00303, LINC00898, LINC00994, LINC01121, LINC01553, and MTOR-AS1 as potentially relevant for the stimulation of cell proliferation mediated by GnRHa based on their direct or indirect association with rapidly dividing cells in normal and pathological tissues. Surgery alone failed to alter the expression of these transcripts.ConclusionGiven that lncRNAs can cooperate with chromatin-modifying enzymes to promote epigenetic regulation of genes, GnRHa treatment may act as a surrogate for mini-puberty by triggering the differentiation of Ad spermatogonia via lncRNA-mediated epigenetic effects. Our work provides additional molecular evidence that infertility and azoospermia in cryptorchidism, resulting from defective mini-puberty cannot be cured with successful orchidopexy alone.

Highlights

Long non-coding N-acetyltransferase RNA (RNA) have emerged as key regulators of gene expression in embryonic stem-cell (ESC) self-renewal and differentiation
The results indicate that a large number of Long non-coding RNA (lncRNA) accumulate at low levels in the testes of boys with high infertility risk (HIR) compared to low infertility risk (LIR), and that a substantial fraction of these transcripts is up-regulated by gonadotropin releasing hormone agonist (GnRHa) treatment
LincRNAs downregulated in HIR testes and stimulated after GnRHa treatment are associated with cancer and the transition of ad spermatogonia We previously reported different lncRNA expression in patients with HIR compared to LIR; some of these RNAs participate in epigenetic processes, including Antisense of IGF2R non-protein coding RNA (AIRN), ERICH-AS1, FOXF1 adjacent non-coding developmental regulatory RNA (FENDRR), HOXD antisense growth-associated long non-coding RNA (HAGLR), and Inactive X specific transcripts (XIST) [12]

Summary

Introduction

Long non-coding RNAs (lncRNAs) have emerged as key regulators of gene expression in embryonic stem-cell (ESC) self-renewal and differentiation. In ESCs, lncRNAs are regulated at the genetic level by transcription factor binding to lncRNA gene promoters. A major function of lncRNAs is the regulation of specific gene expression at multiple steps, including the recruitment and expression of basal transcription machinery, post-transcriptional modifications, and epigenetics [1]. Whether the treatment alters the expression of testicular long non-coding RNAs (lncRNAs) is unknown. To gain insight into the effect of GnRHa on testicular lncRNA levels, we re-analyzed an expression dataset generated from testicular biopsies obtained during orchidopexy for bilateral cryptorchidism. Conclusion: Given that lncRNAs can cooperate with chromatin-modifying enzymes to promote epigenetic regulation of genes, GnRHa treatment may act as a surrogate for mini-puberty by triggering the differentiation of Ad spermatogonia via lncRNA-mediated epigenetic effects. Our work provides additional molecular evidence that infertility and azoospermia in cryptorchidism, resulting from defective mini-puberty cannot be cured with successful orchidopexy alone

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