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Distinctive chromatin in human sperm packages genes for embryo development

Nature volume 460, pages 473–478 (2009)Cite this article

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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Figure 1: Profiling of nucleosomes and their modifications at HOXD.
Figure 2: Nucleosome enrichment at imprinted gene clusters, with high H3K4me3 at paternally expressed noncoding RNAs, and paternally demethylated regions.
Figure 3: Developmental promoters in sperm lack DNA methylation, but acquire methylation during development.

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Acknowledgements

We thank B. Dalley for microarray and sequencing expertise, B. Schackmann for oligonucleotides, K. Boucher for statistical analysis, J. Wittmeyer for yeast nucleosomes and helpful comments, and T. Parnell for helpful comments. Financial support was from the Department of Urology (genomics and support of S.S.H.), the Howard Hughes Medical Institute (HHMI) (genomics, biologicals and support of J.P. and H.Z.), CA24014 and CA16056 for core facilities, and the Huntsman Cancer Institute (bioinformatics and support of D.A.N.). B.R.C. is an investigator with the HHMI.

Author Contributions B.R.C., D.T.C. and S.S.H. were involved in the overall design. D.T.C. and S.S.H. were responsible for acquisition of samples, clinical logistics, patient consenting and Institutional Review Board documents. B.R.C., S.S.H., D.A.N. and H.Z. designed detailed molecular and genomics approaches. D.A.N. carried out data processing and array analysis. S.S.H. and D.A.N. performed sequencing analysis. S.S.H. carried out experiments and produced the figures. J.P. carried out immunoblotting and bisulphite sequencing. B.R.C. wrote the manuscript.

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Authors and Affiliations

  1. Department of Oncological Sciences, Howard Hughes Medical Institute, and Huntsman Cancer Institute,

    Saher Sue Hammoud, Haiying Zhang, Jahnvi Purwar & Bradley R. Cairns

  2. Departments of Surgery, IVF and Andrology Laboratories, Obstetrics and Gynecology, and Physiology,

    Saher Sue Hammoud & Douglas T. Carrell

  3. Research Informatics and Bioinformatics Core Facility, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA ,

    David A. Nix

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  1. Saher Sue Hammoud
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Corresponding authors

Correspondence to Douglas T. Carrell or Bradley R. Cairns.

Additional information

The raw unfiltered reads (fastq format) are deposited at the Gene Expression Omnibus (GEO) under the SuperSeries GSE15594, which encompasses the Subseries entries GSE15690 for ChIP-seq data and GSE15701 for ChIP-chip data.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-12 with Legends. (PDF 1294 kb)

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This file contains Supplementary Tables 1-14. (PDF 1358 kb)

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Hammoud, S., Nix, D., Zhang, H. et al. Distinctive chromatin in human sperm packages genes for embryo development. Nature 460, 473–478 (2009). https://doi.org/10.1038/nature08162

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