Abstract
Evidence for transgenerational inheritance of epigenetic information in vertebrates is scarce. Aberrant patterns of DNA methylation in gametes may set the stage for transmission into future generations. Here, we describe a viable hypomorphic allele of dnmt1 in zebrafish that causes widespread demethylation of CpG dinucleotides in sperm and somatic tissues. We find that homozygous mutants are essentially normal, with the exception of drastically impaired lymphopoiesis, affecting both larval and adult phases of T cell development. The phenotype of impaired larval (but not adult) T cell development is transmitted to subsequent generations by genotypically wildtype fish. We further find that about 200 differentially methylated regions in sperm DNA of transmitting and non-transmitting males, including hypermethylated sites associated with runx3 and rptor genes, whose reduced activities are associated with impaired larval T cell development. Our results indicate a particular sensitivity of larval T cell development to transgenerationally inherited epimutations.
Highlights
Evidence for transgenerational inheritance of epigenetic information in vertebrates is scarce
Our results provide evidence for the transgenerational inheritance of aberrant DNA methylation patterns associated with impaired larval T cell development
When mutant sperm fertilize an egg produced by wild-type or dnmt1+/m heterozygous females, developmentally programmed changes of DNA methylation patterns during germ cell development occur in the presence of maternally provided dnmt[1] protein
Summary
Evidence for transgenerational inheritance of epigenetic information in vertebrates is scarce. 1234567890():,; The transgenerational inheritance of epigenetic information is an attractive mechanism by which the phenotypic consequences of exposure of parents to certain environmental conditions could be transmitted to the generation[1,2]. Mice lacking Dnmt[1] die at around day 9.5 of embryonic development[19]; likewise, zebrafish homozygous for a mutant dnmt[1] allele predicted to encode an enzyme with impaired function of the catalytic domain die at 8 days post fertilization (dpf)[20] These findings attest to central cellular function of Dnmt[118], but conceal a possible tissue-specific function of this protein in the adult organism. Our results provide evidence for the transgenerational inheritance of aberrant DNA methylation patterns associated with impaired larval T cell development
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