Distinctive chromatin in human sperm packages genes for embryo development

Abstract

SummaryAs nucleosomes are widely replaced by protamine in mature human sperm, epigenetic contributions of sperm chromatin to embryo development have been considered highly limited. However, we find the retained nucleosomes significantly enriched at loci of developmental importance including imprinted gene clusters, miRNA clusters, HOX gene clusters, and the promoters of stand-alone developmental transcription and signaling factors. Importantly, histone modifications localize to particular developmental loci. H3K4me2 is enriched at certain developmental promoters, whereas large blocks of H3K4me3 localize to a subset of developmental promoters, regions in HOX clusters, certain non-coding RNAs, and generally to paternally-expressed imprinted loci, but not paternally-repressed loci. Notably, H3K27me3 is significantly enriched at developmental promoters that are repressed in early embryos, including many bivalent (H3K4me3/H3K27me3) promoters in embryonic stem cells. Finally, developmental promoters are generally DNA hypomethylated in sperm, but acquire methylation during differentiation. Taken together, epigenetic marking in sperm is extensive, and correlated with developmental regulators.

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

“…As we discussed in the ‘Introduction’ section, there exists some disagreement in the mapping of sperm nucleosome-retaining regions. In the first human dataset (17) the retention prevalence of developmental promoters over the gene poor regions was suggested. Later, a study that utilized fixed chromatin and a smaller amount of micrococcal nuclease concluded that there is a prevalence of the gene-poor regions in the nucleosome fractions (19,20).…”

“…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).…”

Guidance and Self‐Sorting of Active Swimmers: 3D Periodic Arrays Increase Persistence Length of Human Sperm Selecting for the Fittest

“…Even where the seminal parameters are normal, ejaculates showing sperm with high DNA damage have been reported 10, 11. Moreover, various epidemiological studies reporting the methylation status of imprinted genes of sperm from severely infertile men show a significant risk of imprinting disorders in offspring conceived by IVF and ICSI 18, 19, 20, 21, 22, 23, 24, 25, 26. These observations strongly argue that the sperm genome provides an epigenetically poised set of developmental genes that potentially have a crucial effect on embryological growth and development.…”

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

“…Recently, it was found that imprinted loci retain histones in mature sperm, raising the possibility that histone modification can be an imprint. 34 Notably, H3K4me3 is enriched at regions with no methylation in sperm, suggesting that this mark might protect the oocyte-methylated ICRs from methylation in the male germline. 34,35 Figure 1 Chronology of genomic imprinting and various factors involved in the two major steps, establishment and maintenance.…”