Endonuclease-sensitive regions of human spermatozoal chromatin are highly enriched in promoter and CTCF binding sequences

Abstract

During the haploid phase of mammalian spermatogenesis, nucleosomal chromatin is ultimately repackaged by small, highly basic protamines to generate an extremely compact, toroidal chromatin architecture that is critical to normal spermatozoal function. In common with several species, however, the human spermatozoon retains a small proportion of its chromatin packaged in nucleosomes. As nucleosomal chromatin in spermatozoa is structurally more open than protamine-packaged chromatin, we considered it likely to be more accessible to exogenously applied endonucleases. Accordingly, we have used this premise to identify a population of endonuclease-sensitive DNA sequences in human and murine spermatozoa. Our results show unequivocally that, in contrast to the endonuclease-resistant sperm chromatin packaged by protamines, regions of increased endonuclease sensitivity are closely associated with gene regulatory regions, including many promoter sequences and sequences recognized by CCCTC-binding factor (CTCF). Similar differential packaging of promoters is observed in the spermatozoal chromatin of both mouse and man. These observations imply the existence of epigenetic marks that distinguish gene regulatory regions in male germ cells and prevent their repackaging by protamines during spermiogenesis. The ontology of genes under the control of endonuclease-sensitive regulatory regions implies a role for this phenomenon in subsequent embryonic development.

Effect of high fat diet on paternal sperm histone distribution and male offspring liver gene expression

“…Whereas some studies found nucleosomes mainly at gene-poor regions, 18 others report the greatest enrichment at gene-rich regions. 15,16,20 Moreover, gene ontology analysis revealed that histone bound genes were enriched for developmental activity. For example, in human sperm, mononucleosomes are retained at promoter regions of genes encoding developmental transcription factors and signaling molecules.…”

“…However, a small amount of histones (1-10%) is thought to remain in contact with DNA and to shuttle to the next generation of offspring. [15][16][17][18][19][20] Recent studies have also detected specific histone tail modifications at retained histones and the presence of small RNA in sperm. 3,10,16,[19][20][21] After fertilization of the oocyte, protamines are stripped from the paternal genome and nucleosomes are reassembled.…”

Parental epigenetic control of embryogenesis: a balance between inheritance and reprogramming?

“…Several recent studies have shown that histones (and their modifications) retained in human sperm are not randomly distributed, but are instead enriched at regulatory elements of genes [88], [89], [66]. Intriguingly, differential histone modifications associate with functionally distinct set of genes suggesting that transmission of retained histones might guide transcription during early embryonic development [88], [66].…”

Potential Risk of Senescence on Male fertility and Sperm DNA damage on Progeny

“…Varicocele may exacerbate seminal DNA damage directly through increased scrotal temperature or indirectly via increased generation of ROS. Conversely, leukocytoplasmia contributes to an increased generation and secretion of pro-inflammatory cytokines that could change the regulatory mechanisms of spermiogenesis and DNA damage [29] .…”