Distinctive chromatin in human sperm packages genes for embryo development - PubMed (original) (raw)

. 2009 Jul 23;460(7254):473-8.

doi: 10.1038/nature08162. Epub 2009 Jun 14.

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Distinctive chromatin in human sperm packages genes for embryo development

Saher Sue Hammoud et al. Nature. 2009.

Abstract

Because nucleosomes are widely replaced by protamine in mature human sperm, the epigenetic contributions of sperm chromatin to embryo development have been considered highly limited. Here we show that the retained nucleosomes are significantly enriched at loci of developmental importance, including imprinted gene clusters, microRNA clusters, HOX gene clusters, and the promoters of stand-alone developmental transcription and signalling factors. Notably, histone modifications localize to particular developmental loci. Dimethylated lysine 4 on histone H3 (H3K4me2) is enriched at certain developmental promoters, whereas large blocks of H3K4me3 localize to a subset of developmental promoters, regions in HOX clusters, certain noncoding RNAs, and generally to paternally expressed imprinted loci, but not paternally repressed loci. Notably, trimethylated H3K27 (H3K27me3) is significantly enriched at developmental promoters that are repressed in early embryos, including many bivalent (H3K4me3/H3K27me3) promoters in embryonic stem cells. Furthermore, 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.

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Figures

Figure 1

Figure 1

Developmental genes are associated with particular chromatin attributes in human sperm. GoMiner was used to identify enriched categories, and all categories displayed have an FDR < 0.01. The top five general categories are listed, after omitting nearly identical/redundant classes. An expanded GO table with the unfiltered top 30-60 categories, the total genes, number of changed genes, enrichment, and FDR are provided in the Supplemental Material.

Figure 2

Figure 2

Profiling of nucleosomes and their modifications at HOXD. For high-throughput sequencing, we display the mapped sequencing reads from D1 or a donor pool (red or orange bars; normalized difference score), and their significance (green or blue bars; FDR of 20 is <1% and FDR of 30 is <0.1%). a, The HOXD locus (black box) and an uncharacterized flanking locus (green oval). b, Profiling of nucleosome modifications at HOXD (in part a). The y-axis is signal intensity (log2, for ChIP-chip), or the normalized difference score for sequencing. The regions not tiled on the array are underlined in red.

Figure 3

Figure 3

Nucleosomes enrichment at imprinted gene clusters, with high H3K4me3 at paternally-expressed non-coding RNAs, and paternally-demethylated regions. a, Histone enrichment at the 11p15.5 imprinted cluster (ending near OSBPL5), but not in the adjacent region. b and c, An expanded view of the DMRs (yellow rectangles) of H19 (paternally-methylated) and MEST (paternally-demethylated). d, High H3K4me3 at the promoters of the paternally-expressed genes BEGAIN, DLK1, and RTL, and the lack of H3K4me3 at the methylated intergenic-differentially methylated region (IG-DMR) of GTL2 in sperm. Notably, both H3K4me3 and H3K27me3 reside at the promoter of GTL2, which later acquires methylation in the embryo.

Figure 4

Figure 4

Developmental promoters in sperm lack DNA methylation, but acquire methylation during development. a, DNA methylation of the HOXD locus in the mature sperm (blue bars) or primary fibroblasts (orange line overlay). The y-axis is the signal intensity (log2) and the x-axis is the annotated physical map (HG17). The regions not tiled on the array are underlined in red.

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