Repressive and active histone methylation mark distinct promoters in human and mouse spermatozoa

Abstract

In higher eukaryotes, histone methylation is involved in maintaining cellular identity during somatic development. As most nucleosomes are replaced by protamines during spermatogenesis, it is unclear whether histone modifications function in paternal transmission of epigenetic information. Here we show that two modifications important for Trithorax- and Polycomb-mediated gene regulation have methylation-specific distributions at regulatory regions in human spermatozoa. Histone H3 Lys4 dimethylation (H3K4me2) marks genes that are relevant in spermatogenesis and cellular homeostasis. In contrast, histone H3 Lys27 trimethylation (H3K27me3) marks developmental regulators in sperm, as in somatic cells. However, nucleosomes are only moderately retained at regulatory regions in human sperm. Nonetheless, genes with extensive H3K27me3 coverage around transcriptional start sites in particular tend not to be expressed during male and female gametogenesis or in preimplantation embryos. Promoters of orthologous genes are similarly modified in mouse spermatozoa. These data are compatible with a role for Polycomb in repressing somatic determinants across generations, potentially in a variegating manner.

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

“…Nevertheless, in human and mouse approximately 10 and 1% of histones are retained in spermatozoa respectively [66]. Since these retained histones harbor post-translational modifications, as in somatic cells, they may function as mediators of epigenetic inheritance between generations.…”

“…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]. …”

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

“…The evidence for this mechanism comes from histone retention studies in sperm, with 10% of the haploid genome in humans and 1% in mice being able to retain the nucleosomes (16). These nucleosome-protected regions are of great interest because they can potentially mediate transgenerational epigenetic inheritance.…”

“…The first high-resolution genome-wide map of human spermatozoa histones shows a strong enrichment in methylated histone H3K4me3 at many promoters of developmental genes, genes encoding signaling factors, imprinted gene clusters, microRNA and HOX gene clusters (17). These studies showed that the promoters in sperm are enriched in H3K4me3 and H3K27me3, and it was suggested that genes with these marks play a particularly important role in epigenetic inheritance (16–18). On the other hand, more recent nucleosome mapping studies showed that sperm nucleosome fraction is enriched in gene-poor regions and is generally depleted from the promoters (19,20).…”

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

“…[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. 22 It remains to be shown whether H3 retention in sperm can transfer transgenerational epigenetic information.…”