Dissecting methylation errors at imprinted genes in human spermatozoa: from molecular observations to clinical applications

Epigenetic modifications regulate chromatin conformation and transcription factor accessibility to regulatory regions of the genome, controlling gene expression without altering the DNA sequence itself, and being stably transmitted throughout cell divisions. One of the most well studied epigenetic marks is DNA methylation, which controls the monoallelic, parental-origin dependent expression of imprinted genes. Paternal imprinting marks are established in the male germ line, so that mature gametes-the spermatozoa-transmit correct imprints to the future embryo. Anomalies in the establishment and/or maintenance of imprinting marks can interfere with embryonic and placental development and/or result in the birth of children affected by imprinting syndromes, such as Silver-Russell and Beckwith-Wiedemann. Here, we review the literature on the observations of imprinting errors in the male gamete, in the context of disturbances in spermatogenesis resulting in male infertility, focusing on the observations described by our group and others. We provide a clinical perspective on the implementation of sperm methylation analysis as a tool to improve diagnostic and therapeutic strategies in Assisted Reproduction Technologies and highlight the importance of understanding the molecular mechanisms underlying spermatogenic defects and male infertility.