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Genomics Study Suggests Sperm Chromatin May Influence Embryo Development

NEW YORK (GenomeWeb News) – The nature and distribution of chromatin sub-units in the sperm genome may influence embryonic development, according to a study appearing online yesterday in Nature.

A team of Utah researchers used ChIP-chip, ChIP-seq, and other genomic approaches to examine the distribution of nucleosomes, particularly modified histones, in sperm samples from four fertile men. Their results suggest that histone modifications are clustered in parts of the genome that will eventually contribute to embryonic development, suggesting sperm DNA packaging is important to this process.

"Our findings show that the father plays an active role in packaging his genome to help ensure a healthy baby," co-senior author Brad Cairns, a researcher affiliated with the Howard Hughes Medical Institute and the University of Utah's Huntsman Cancer Institute, said in a statement. "However, they also raise the possibility that a man's aging, health, and lifestyle may alter this packaging and negatively affect fertility and embryo development."

The results suggest scientists may have previously underestimated the importance of sperm chromatin in epigenetics based on the limited number of nucleosomes in the genome. Just four percent or so of the haploid sperm genome has nucleosomes. The rest are replaced by DNA-packaging proteins called protamines, which are themselves thought to contribute to sperm function, during sperm cell differentiation.

But when Cairns and his team used several genomic approaches to characterize the nature and distribution of these nucleosomes, they found clues suggesting that nucleosomes that persist in the sperm genome could be functionally important.

The team got sperm samples from four fertile men visiting the University of Utah Andrology lab, isolated DNA, and did chromatin immunoprecipitation experiments using antibodies to various histones. Next, they used either high-throughput sequencing with an Illumina Genome Analyzer II or high-density promoter tiling arrays to look at where the nucleosomes were in the genome.

The researchers found 9,841 regions in the sperm genome enriched for histones. Of these, more than three quarters fell within gene regions, suggesting the histones might be functional rather than randomly peppered throughout the genome.

Nearly 1,700 of the genes enriched for nucleosomes have developmental roles, according to their Gene Ontology profiles. The enrichment at developmental loci was modest but widespread, the team noted. They also detected numerous nucleosomes at or near microRNA promoters and imprinted genes.

When the researchers used ChIP-chip and ChIP-seq to delve into the sorts of histone modification patterns present in the sperm genome, they found distinct histone modifications cropping up at different spots in the genome.

For instance, dimethylated lysine 4 histone H3 (H3K4me2) was frequently found at the promoters of transcription factor that regulate developmental genes — a distinct localization from that observed in somatic cells, where H3K4me2 typically localizes to euchromatic parts of the genome, the authors noted.

They found a second modified histone, H3K4me3, at several nuclear architecture, RNA metabolism, and spermatogenesis genes. In contrast, H3K4me3 seems to spend most of its time at transcription start sites and poised RNA Polymerase II in somatic cells.

Yet another histone overlapped with its previously characterized localization sites in embryonic stem cells. This localization apparently represses the promoters in the sperm, early embryo, and embryonic stem cells. And promoter occupancy was frequently linked to low methylation levels, based on the team's methylated DNA immunoprecipitation, or MeDIP, experiments. Results from such studies were verified using qPCR or bisulfite sequencing.

Nucleosomes were also plentiful at HOX loci — clusters of homeobox genes involved in development. These nucleosomes harbored distinct "regional" modifications, the authors noted, with patterns that were quite different from those observed in embryonic stem cells, both in terms of the types of histone modifications present and their distribution.

In addition, the team detected histone enrichment at miRNA genes and clusters, particularly those involved in embryonic development.

The location of histone modifications offered clues about gene imprinting as well. For instance, H3K4me3 was enriched at paternally expressed genes and non-coding RNAs while H3K9me3 was usually found at paternally silenced genes. Other regions were marked by two different histone modifications simultaneously.

"Taken together, we reveal chromatin features in sperm that may contribute to totipotency, developmental decisions, and imprinting patterns," the authors concluded, "and open new questions about whether aging and lifestyle affects chromatin in a manner that impacts fertility or embryo development."

That, in turn, may ultimately have implications for those looking for fertility information and/or treatment. Cairns expressed enthusiasm about the prospects of coming up with a diagnostic test for couples with fertility problems based on this and other research.

"We are hopeful that this work will soon lead to a clinical diagnostic test that will help couples with infertility problems make better informed decisions regarding their prospects for a healthy child," Cairns said.

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