In many studies spatial and temporal expression
In many studies, spatial and temporal expression and subcellular localizations of the DNMTs are examined in greater detail. These studies are evaluated and discussed in the remaining part of the article. DNMT1 protein expression was characterized in the genital ridge of the primitive mouse gonad at E11.5 (La Salle et al., 2004). DNMT1 was localized both nuclear and cytoplasmic, and it also surrounded the mitotic chromosomes at the genital ridge of E11.5. In male germ cells, Dnmt1 mRNA is also highly expressed in the gonocytes of testicular tissue at 12.5–14.5 days post-coitus (dpc) of early development, but its expression is surprisingly down-regulated at 16.5–18.5 dpc in mice (Sakai et al., 2001) (). It is important to note that the genomic imprinting establishment of the maternally expressed H19 (Imprinted Maternally Expressed Transcript) gene in gonocytes is achieved at around 16.5 dpc (Tada et al, 1998, Ueda et al, 2000), and genome-wide DNA methylation is given rise at 16.5–18.5 dpc (Coffigny et al., 1999) in contrast to the remarkably decreased Dnmt1 gene expression at these time points (Sakai et al., 2001). Most likely, not only DNMT1 but also other DNMT such as DNMT3A and DNMT3A seem to be responsible for establishing DNA methylation patterns during early development. DNMT1 particularly plays a role in the maintenance of the methylation process; therefore, the Dnmt1 gene is highly expressed in the proliferating 1027 australia (Szyf et al., 1991). Consistently, Sakai et al. (2001) found that Dnmt1 shows an expressional correlation with the cell proliferation marker, proliferating cell nuclear antigen (PCNA) in testicular cells (Sakai et al., 2001) complying with the presence of a physical interaction of DNMT1 with PCNA (Chuang et al., 1997). In addition to the presence of DNMT1 expression in embryonic testis tissues, it is also expressed in the postnatal mouse testes, at higher levels than that of prenatal ones (La Salle et al., 2004). In contrast, both DNMT3A and DNMT3L protein expression were found to be at very high levels between E13.5 and 18.5, suggesting that these enzymes are important for prenatal testis development and responsible for the establishment of the DNA methylation patterns in male germ line cells (La Salle et al., 2004) ().
Expression of DNMTs in germ-line cells during spermatogenesis
DNMTs and male infertility Infertility is a worldwide reproductive problem that affects 13–18% of couples, who cannot conceive despite unprotected intercourse during one year, and it arises from either the male factor or the female factor or both male and female factors (Dube et al, 2008, Gnoth et al, 2005). The male factor-associated infertility comprises half of the infertile couples (Dube et al., 2008). Azoospermia, one of the commonly encountered reasons for male infertility is briefly defined as complete absence of functional sperm in the ejaculate, and it affects 10–15% of infertile men (Hamada et al, 2013, Jarow et al, 1989). Azoospermia is generally divided into two subgroups: obstructive azoospermia resulting from obstruction of the genital duct and non-obstructive azoospermia derived from testicular failure (Wosnitzer et al., 2014). Other infertility-associated spermatogenetic defects such as reduced sperm concentration (oligospermia), defective sperm motility (asthenozoospermia) and distorted sperm morphology (teratozoospermia) are encountered in IVF clinics (Friemel et al., 2014). Oligozoospermia is characterized by low concentration of spermatozoa in ejaculated semen. According to the World Health Organization (WHO), normal ejaculated semen includes approximately 60 million sperm/ml, but in oligozoospermic men it is identified as a concentration of less than 20 million sperm/ml in ejaculate. Because spermatogenesis is a complex process consisting of spermatogonia, meiosis and differentiation stages, DNA methylation is one of the epigenetic mechanisms playing an important role for normal spermatogenesis (Marchal et al, 2004, Rajender et al, 2011). It has been reported that abnormal DNA methylation in spermatogenic cells due to genetic failure, environmental factors and disturbed expression of the DNMTs (Massart et al, 2012, Toshimori et al, 2004) may lead to spermatogenetic impairments (Hartmann et al, 2006, Takashima et al, 2009) (). As a result, hypomethylation or hypermethylation of the target DNA strands might negatively influence the process of spermatogonial cell differentiation into spermatozoa, resulting in subfertility or infertility (Kobayashi et al, 2007, Raman, Narayan, 1995) ().