ESPE2023 Rapid Free Communications Sex differentiation, gonads and gynaecology or sex endocrinology (6 abstracts)
1Cryptorchidism research institute, Liestal, Switzerland. 2Children’s Surgery Centre, Faculty of Medicine, Vilnius University, 01513 Vilnius, Lithuania., Vilnius, Lithuania. 3FMI. Basel, Basel, Switzerland
Introduction: Multiple studies have demonstrated that histone lysine methyltransferases regulate gene transcription, thereby influencing cell proliferation, cell differentiation, cell migration, and tissue invasion.
Aim of the study: Here we describe the key functions of histone lysine methyltransferases and chromatin remodeling genes and summarize their role in infertility.
Patients and Methods: The patients, biopsy samples, histological analyses, and RNA sequencing protocol were described in detail in the previous study.(1) Here, we interpreted the gene expression patterns observed in different prepubertal testicular cell types using our own RNA profiling data. Cryptorchid boys with defective mini-puberty and impaired differentiation of Ad spermatogonia (High Infertility Risk) compared to patients with intact differentiation of gonocytes into Ad spermatogonia (Low Infertility Risk).
Gene symbol | -/+ GnRHa treatment (RPKM) | log2FC/FDR |
Class 1 | ||
KDM6A | 19.9/11.3 | -0.81/0.0009 |
TET1 | 11.9/7.1 | -0.73/0.002 |
Class 2 | ||
ARID4A | 12.5/9 | -0.48/0.03 |
ARID5B | 21.6/15.3 | -0.49/0.03 |
ATRX | 33.7/19.3 | -0.79/0.002 |
DNMT3A | 24.6/19.86 | n.s. |
EPC1 | 23.0/14.1 | -0.7/0.002 |
HDAC1 | 22.2/12.7 | -0.80/0.0008 |
HDAC2 | 15.5/9.7 | -0.67/0.004 |
HDAC3 | 22.2/16.2 | -0.45/0.045 |
HDAC8 | 7.7/5.7 | -0.48/0.052 |
INO80D | 12.1/7.9 | -0.60/0.01 |
KDM4A | 27.6/20.3 | -0.44/0.052 |
KMT2E | 35.8/24.2 | -0.56/0.02 |
PBRM1 | 27.2/16.6 | -0.7/0.004 |
PRMT2 | 27.5/16.9 | -0.69/0.004 |
SETD7 | 22.3/12.3 | -0.85/0.0006 |
SMARCA1 | 96.2/52.6 | -0.87/0.0004 |
SMARCA2 | 37.3/24.0 | -0.87/0.0009 |
TSPYL4 | 12.4/9.2 | -0.43/0.054 |
Class 3 | ||
ARID2 | 19.3/11.6 | -0.72/0.003 |
ASH1L | 43.3/36.8 | -0.62/0.01 |
BAZ2B | 47.0/27.6 | -0.76/0.003 |
SCML2 | 26.3/14.5 | -0.85/0.0005 |
SETD2 | 40.0/24.5 | -0.7/0.005 |
TRDMT1 | 4.89/3.5 | -0.45/0.048 |
Results: HIR samples have altered expression of several genes encoding histone methyltransferases and together with the diminished expression of histone deacetylases and increased expression of HDAC8 decrotonylase, indicating altered histone marks and, thus, a perturbed histone code. Curative GnRHa treatment induces normalization of histone methyltransferase, chromatin remodeling, and histone deacetylase gene expression. (Table 1) If 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 observations indicate that Linc00261, FENDRR, HOTAIR, and FOXA1 participate in the alternate pathway for curative GnRHa treatment to rescue impaired fertility.
Conclusions: Our findings suggest that epigenetic mechanisms are critical to better understanding the root causes underlying male infertility related to cryptorchidism and its possible transgenerational transmission.