Genome-wide chromatin analysis in mature mouse and human spermatozoa

Most human aneuploidies originate maternally, due in part to the presence of highly stringent checkpoints during male meiosis. Indeed, male sterility is common among aneuploid mice used to study chromosomal abnormalities, and male germline transmission of exogenous DNA has been rarely reported. Here we show that, despite aberrant testis architecture, males of the aneuploid Tc1 mouse strain produce viable sperm and transmit human chromosome 21 to create aneuploid offspring. In these offspring, we mapped transcription, transcriptional initiation, enhancer activity, non-methylated DNA, and transcription factor binding in adult tissues. Remarkably, when compared with mice derived from female passage of human chromosome 21, the chromatin condensation during spermatogenesis and the extensive epigenetic reprogramming specific to male germline transmission resulted in almost indistinguishable patterns of transcriptional deployment. Our results reveal an unexpected tolerance of aneuploidy during mammalian spermatogenesis, and the surprisingly robust ability of mouse developmental machinery to accurately deploy an exogenous chromosome, regardless of germline transmission.DOI: http://dx.doi.org/10.7554/eLife.20235.001

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“…Mouse sperm was obtained from male mice at an age between 16–32 weeks according to Hisano et al (2013) and quantified using a hemocytometer.…”

Section: Methodsmentioning

confidence: 99%

Successful transmission and transcriptional deployment of a human chromosome via mouse male meiosis

Ernst

Pike

Aitken

et al. 2016

eLife

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“…ChIP-sequencing experiments were performed as described before (17,32) using an antibody against H3K4me2 (Millipore 07-030). ChIP-seq libraries were prepared using Illumina ChIP-seq DNA Sample Prep Kit (Cat# IP-102-1001) and sequenced on Illumina GA II.…”

Section: Chip Sequencingmentioning

confidence: 99%

Disruption of histone methylation in developing sperm impairs offspring health transgenerationally

Siklenka

Erkek

Godmann

et al. 2015

Science

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464

367

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A father's lifetime experiences can be transmitted to his offspring to affect health and development. However, the mechanisms underlying paternal epigenetic transmission are unclear. Unlike in somatic cells, there are few nucleosomes in sperm, and their function in epigenetic inheritance is unknown. We generated transgenic mice in which overexpression of the histone H3 lysine 4 (H3K4) demethylase KDM1A (also known as LSD1) during spermatogenesis reduced H3K4 dimethylation in sperm. KDM1A overexpression in one generation severely impaired development and survivability of offspring. These defects persisted transgenerationally in the absence of KDM1A germline expression and were associated with altered RNA profiles in sperm and offspring. We show that epigenetic inheritance of aberrant development can be initiated by histone demethylase activity in developing sperm, without changes to DNA methylation at CpG-rich regions.

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“…Chromatin fractionation and chromatin immunoprecipitation (ChIP) were performed as described before Hisano et al 2013) with slight modifications. Pretreatment of sperm cells with DTT was omitted, and chromatin was digested with 2.5 U of MNase/1 million of cells (Roche, #12533700) for 30 min at 37°C.…”

Section: Preparation Of Chip-seq Samplesmentioning

confidence: 99%

Sperm is epigenetically programmed to regulate gene transcription in embryos

et al. 2016

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For a long time, it has been assumed that the only role of sperm at fertilization is to introduce the male genome into the egg. Recently, ideas have emerged that the epigenetic state of the sperm nucleus could influence transcription in the embryo. However, conflicting reports have challenged the existence of epigenetic marks on sperm genes, and there are no functional tests supporting the role of sperm epigenetic marking on embryonic gene expression. Here, we show that sperm is epigenetically programmed to regulate embryonic gene expression. By comparing the development of sperm- and spermatid-derived frog embryos, we show that the programming of sperm for successful development relates to its ability to regulate transcription of a set of developmentally important genes. During spermatid maturation into sperm, these genes lose H3K4me2/3 and retain H3K27me3 marks. Experimental removal of these epigenetic marks at fertilization de-regulates gene expression in the resulting embryos in a paternal chromatin-dependent manner. This demonstrates that epigenetic instructions delivered by the sperm at fertilization are required for correct regulation of gene expression in the future embryos. The epigenetic mechanisms of developmental programming revealed here are likely to relate to the mechanisms involved in transgenerational transmission of acquired traits. Understanding how parental experience can influence development of the progeny has broad potential for improving human health.

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Genome-wide chromatin analysis in mature mouse and human spermatozoa

Cited by 80 publications

References 29 publications

Successful transmission and transcriptional deployment of a human chromosome via mouse male meiosis

Successful transmission and transcriptional deployment of a human chromosome via mouse male meiosis

Disruption of histone methylation in developing sperm impairs offspring health transgenerationally

Sperm is epigenetically programmed to regulate gene transcription in embryos

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