Disruption of histone methylation in developing sperm impairs offspring health transgenerationally
Generations affected by histone changes
Parent and even grandparent environmental exposure can transmit adverse health effects to offspring. The mechanism of transmission is unclear, but some studies have implicated variations in DNA methylation. In a mouse model, Siklenka et al. found that alterations in histone methylation during sperm formation in one generation leads to reduced survival and developmental abnormalities in three subsequent generations (see the Perspective by McCarrey). Although changes in DNA methylation were not observed, altered sperm RNA content and abnormal gene expression in offspring were measured. Thus, chromatin may act as a mediator of molecular memory in transgenerational inheritance.
Science, this issue p. 10.1126/science.aab2006; see also p. 634
Structured Abstract
INTRODUCTION
Despite the father transmitting half of the heritable information to the embryo, the focus of preconception health has been the mother. Paternal effects have been linked to complex diseases such as cancer, diabetes, and obesity. These diseases are increasing in prevalence at rates that cannot be explained by genetics alone and highlight the potential for disease transmission via nongenetic inheritance, through epigenetic mechanisms. Epigenetic mechanisms include DNA methylation, posttranslational modifications of histones, and noncoding RNA. Studies in humans and animals suggest that epigenetic mechanisms may serve in the transmission of environmentally induced phenotypic traits from the father to the offspring. Such traits have been associated with altered gene expression and tissue function in first and second offspring generations, a phenomenon known as intergenerational or transgenerational inheritance, respectively. The mechanisms underlying such paternal epigenetic transmission are unclear.
RATIONALE
Sperm formation involves rapid cell division and distinctive transcription programs, resulting in a motile cell with highly condensed chromatin. Within the highly compacted sperm nucleus, few histones are retained in a manner that suggests an influential role in development. Despite being the major focus of studies in epigenetic inheritance, the role of DNA methylation in paternal epigenetic inheritance is unresolved, as only minor changes in DNA methylation in sperm at CpG-enriched regions have been associated with transmission of environmentally induced traits. Instead, there may be a combination of molecular mechanisms underlying paternal transgenerational epigenetic inheritance involving changes in histone states and/or RNA in sperm. The function of sperm histones and their modifications in embryonic development, offspring health, and epigenetic inheritance is unknown. By overexpressing the human KDM1A histone lysine 4 demethylase during mouse spermatogenesis, we generated a mouse model producing spermatozoa with reduced H3K4me2 within the CpG islands of genes implicated in development, and we studied the development and fitness of the offspring.
RESULTS
Male transgenic offspring were bred with C57BL/6 females, generating the experimental heterozygous transgenic (TG) and nontransgenic (nonTG) brothers. Each generation from TG and nonTG animals (F1 to F3 in our transgenerational studies) was bred with C57BL/6 females, and the offspring (pups from generations F1 to F4) were analyzed for intergenerational and transgenerational effects. We found that KDM1A overexpression in one generation severely impaired development and survivability of offspring. These defects lasted for two subsequent generations in the absence of KDM1A germline expression. We characterized histone and DNA methylation states in the sperm of TG and nonTG sires. Overexpression of KDM1A was associated with a specific loss of H3K4me2 at more than 2300 genes, including many developmental regulatory genes. Unlike in other examples of paternal transgenerational inheritance, we observed no changes in sperm DNA methylation associated with primarily CpG-enriched regions. Instead, we measured robust and analogous changes in sperm RNA content of TG and nonTG descendants, as well as in their offspring, at the two-cell stage. These changes in expression and the phenotypic abnormalities observed in offspring correlated with altered histone methylation levels at genes in sperm. This study demonstrates that KDM1A activity during sperm development has major developmental consequences for offspring and implicates histone methylation and sperm RNA as potential mediators of transgenerational inheritance. Our data emphasize the complexity of transgenerational epigenetic inheritance likely involving multiple molecular factors, including the establishment of chromatin states in spermatogenesis and sperm-borne RNA.
CONCLUSION
Correct histone methylation during spermatogenesis is critical for offspring development and survival over multiple generations. These findings demonstrate the potential of histone methylation as a molecular mechanism underlying paternal epigenetic inheritance. Its modification by environmental influences may alter embryo development and complex disease transmission across generations. An essential next step is to establish functional links between environmental exposures, the composition of the sperm epigenome, and consequent altered gene expression and metabolic processes in offspring. Considering the mounting evidence, it may soon be reasonable to suggest that future fathers protect their sperm epigenome.
Disruption of histone methylation in developing sperm by exposure to the KDM1A transgene in one generation severely impaired development and survivability of offspring.
These defects were transgenerational and occurred in nonTG descendants in the absence of KDM1A germline expression. Developmental defects in offspring and embryos were associated with altered RNA expression in sperm and embryos.
Abstract
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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Supplementary Material
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Science
Volume 350 | Issue 6261
6 November 2015
6 November 2015
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Copyright © 2015, American Association for the Advancement of Science.
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Received: 26 March 2015
Accepted: 18 September 2015
Published in print: 6 November 2015
Acknowledgments
We thank M. Stadler, H. Royo, and D. Gaidatzis (FMI) for advice on computational data analysis; B. K. Hall (Dalhousie University) and J. Tanny and D. Bernard (McGill University) for advice; X. Giner for technical expertise; the Laboratoire de Transgénèse Center de Recherché, Centre Hospitalier de l’Université de Montréal, Canada, for microinjection and generation of the transgenic hKDM1A founders; Y. Shi (Harvard University) for providing full-length human KDM1 cDNA; T. Pastinen, G. Bourque, M. Caron, and platform personnel of the McGill Epigenomics Mapping and Data Coordinating Centers in the McGill University, as well as Génome Québec Innovation Centre, for setting up the RRBS sequencing data analysis pipeline; and F. Lefebvre for support with microarray analysis. This research was funded by the Canadian Institute of Health Research (S.K. and J.T.), Genome Quebec (S.K. and J.T.), the Reseau de Reproduction Quebecois, Fonds de Recherche du Québec – Nature et Technologies (FRQNT) (S.K. and J.T), Boehringer Ingelheim Fond (S.E.), Swiss National Science Foundation (grant 31003A_125386) (A.H.F.M.P.), and the Novartis Research Foundation (A.H.F.M.P.). The data reported in this paper are available at Gene Expression Omnibus: Microarray data, including both the CEL files and the transcript-level expression values, are under accession number GSE66052; ChIP-seq and nucleosome data are under accession number GSE55471. K.S., S.E., M.G., R.L., S.M., J.T., A.H.F.M.P., and S.K. conceived and designed the experiments. K.S., S.E., M.G., R.L., C.L., T.C., S.M., J.X., J.T., M.S., A.H.F.M.P., and S.K. performed the experiments and analyzed the data. M.H. provided advice on the data analysis and the manuscript. K.S., J.T., A.H.F.M.P., and S.K. wrote the manuscript. We declare no conflicts of interest that would prejudice the impartiality of this work.
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