DNA methyltransferase inhibitors modulate histone methylation: epigenetic crosstalk between H3K4me3 and DNA methylation during sperm differentiation

Abstract

Summary The process of cytodifferentiation in spermatogenesis is governed by a unique genetic and molecular programme. In this context, accurate ‘tuning’ of the regulatory mechanisms involved in germ cells differentiation is required, as any error could have dramatic consequences on species survival and maintenance. To study the processes that govern the spatial–temporal expression of genes, as well as analyse transmission of epigenetic information to descendants, an integrated approach of genetics, biochemistry and cytology data is necessary. As information in the literature on interplay between DNA methylation and histone H3 lysine 4 trimethylation (H3K4me3) in the advanced stages of murine spermatogenesis is still scarce, we investigated the effect of a DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine, at the cytological level using immunocytochemistry methodology. Our results revealed a particular distribution of H3K4me3 during sperm cell differentiation and highlighted an important role for regulation of DNA methylation in controlling histone methylation and chromatin remodelling during spermatogenesis.

Epigenetics and Testicular Cancer: Bridging the Gap Between Fundamental Biology and Patient Care

“…Moreover, the aberrant regulation of H3 modifications leads to germ cell apoptosis, infertility, and defective spermiogenesis (Yuen et al, 2014). Our previous studies have shown a unique pattern of H3 methylation in male germ cells, illustrating epigenetic crosstalk between H3K4me3 and DNA methylation during spermatogenesis (Burlibaşa et al, 2021).…”

“…methylation has stage-specific distribution, while in nonseminoma, histone H3K4 and H3K9 methylation has been detected in all cellular stages (Lambrot et al, 2012;Vega et al, 2012;Burlibaşa et al, 2021). This suggests an association between methylation of histone H3K4/H3K9 and abnormal gene expression in non-seminoma.…”

H3 histone methylation landscape in male urogenital cancers: from molecular mechanisms to epigenetic biomarkers and therapeutic targets

“…Methylation of H3K4, particularly the H3K4me3 mark, has a stage-specific distribution in normal testis, but not in TGCTs (Vega et al, 2012;Burlibaşa et al, 2021). High levels of H3K4 methylation are present in GCNIS, as well as in non-seminoma, which, according to Singh et al (2021), could be related to the proliferative capacity by preventing DNA methylation, which is necessary for differentiation (Singh et al, 2021).…”

Recent progress in DNA methyltransferase inhibitors as anticancer agents

“…Studies showed that 5-azacytidine could inhibit the L1210 cell with ID50 and ID90 of 0.019 and 0.15 μg/ml in vitro , respectively ( Li et al, 1970 ). In addition, a study showed that 5-azacitidine can significantly increase the tri-methylation of lysine-4 on histone H3 in mouse primary spermatocytes, which indicated that 5-azacitidine could modulate histone methylation ( Burlibaşa et al, 2021 ). It could also reduce tumor growth in two intracerebral glioblastoma models in vivo .…”