disruption of histone methylation in developing sperm impairs offspring health transgenerationally
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ABSTRACT STRUCTURED ABSTRACT EDITOR'S SUMMARY
Sciencewww.sciencemag.orgPublished Online October 8 2015Science 6 November 2015: Vol. 350 no. 6261 DOI: 10.1126/science.aab2006
RESEARCH ARTICLE
Disruption of histone methylation in developing sperm impairsoffspring health transgenerationally
Keith Siklenka1,*, Serap Erkek2,3,*,†,‡, Maren Godmann4,§, Romain Lambrot4, Serge McGraw5||,
Christine Lafleur4, Tamara Cohen4, Jianguo Xia4,6, Matthew Suderman7, Michael Hallett8,
Jacquetta Trasler5,9, Antoine H. F. M. Peters2,3,*,¶, Sarah Kimmins1,4,*,¶
Author Affiliations
Author Notes
↵¶Corresponding author. E-mail: [email protected] (S.K.); [email protected] (A.H.F.M.P.)
↵* These authors contributed equally to this work.
INTRODUCTION
Despite the father transmitting half of the heritable information to the embryo, the focus ofpreconception health has been the mother. Paternal effects have been linked to complex diseasessuch as cancer, diabetes, and obesity. These diseases are increasing in prevalence at rates thatcannot be explained by genetics alone and highlight the potential for disease transmission vianongenetic inheritance, through epigenetic mechanisms. Epigenetic mechanisms include DNAmethylation, posttranslational modifications of histones, and noncoding RNA. Studies in humansand animals suggest that epigenetic mechanisms may serve in the transmission ofenvironmentally induced phenotypic traits from the father to the offspring. Such traits have beenassociated with altered gene expression and tissue function in first and second offspringgenerations, 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 amotile cell with highly condensed chromatin. Within the highly compacted sperm nucleus, fewhistones are retained in a manner that suggests an influential role in development. Despite beingthe major focus of studies in epigenetic inheritance, the role of DNA methylation in paternalepigenetic 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 paternaltransgenerational epigenetic inheritance involving changes in histone states and/or RNA in sperm.The function of sperm histones and their modifications in embryonic development, offspringhealth, and epigenetic inheritance is unknown. By overexpressing the human KDM1A histonelysine 4 demethylase during mouse spermatogenesis, we generated a mouse model producingspermatozoa with reduced H3K4me2 within the CpG islands of genes implicated in development,and we studied the development and fitness of the offspring.
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PERSPECTIVEEPIGENETICS
The epigenome—a familyaffairJohn R. McCarreyScience 6 November 2015: 634-635.
RESULTS
Male transgenic offspring were bred with C57BL/6 females, generating the experimentalheterozygous transgenic (TG) and nontransgenic (nonTG) brothers. Each generation from TGandnonTG animals (F1 to F3 in our transgenerational studies) was bred with C57BL/6 females, and theoffspring (pups from generations F1 to F4) were analyzed for intergenerational andtransgenerational effects. We found that KDM1A overexpression in one generation severelyimpaired development and survivability of offspring. These defects lasted for two subsequentgenerations in the absence of KDM1A germline expression. We characterized histone and DNAmethylation states in the sperm of TG and nonTG sires. Overexpression of KDM1A was associatedwith a specific loss of H3K4me2 at more than 2300 genes, including many developmentalregulatory genes. Unlike in other examples of paternal transgenerational inheritance, we observedno 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 thephenotypic abnormalities observed in offspring correlated with altered histone methylation levelsat genes in sperm. This study demonstrates that KDM1A activity during sperm development hasmajor developmental consequences for offspring and implicates histone methylation and spermRNA as potential mediators of transgenerational inheritance. Our data emphasize the complexityof transgenerational epigenetic inheritance likely involving multiple molecular factors, includingthe establishment of chromatin states in spermatogenesis and sperm-borne RNA.
CONCLUSION
Correct histone methylation during spermatogenesis is critical for offspring development andsurvival over multiple generations. These findings demonstrate the potential of histonemethylation as a molecular mechanism underlying paternal epigenetic inheritance. Its modificationby environmental influences may alter embryo development and complex disease transmissionacross generations. An essential next step is to establish functional links between environmentalexposures, the composition of the sperm epigenome, and consequent altered gene expressionand metabolic processes in offspring. Considering the mounting evidence, it may soon bereasonable to suggest that future fathers protect their sperm epigenome.
Disruption of histone methylation in developingsperm by exposure to the KDM1A transgene in onegeneration severely impaired development andsurvivability of offspring.
These defects were transgenerational and occurred innonTG descendants in the absence of KDM1Agermline expression. Developmental defects inoffspring and embryos were associated with alteredRNA expression in sperm and embryos.
Received for publication 26 March 2015.Accepted for publication 18 September 2015.
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PERSPECTIVEEPIGENETICSThe epigenome—a family affairJohn R. McCarrey
Science 6 November 2015: 634-635.Summary Full Text Full Text (PDF)