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Transgenerational inheritance of impaired larval T cell development in zebrafish.

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.

SUBMITTER: Iwanami N

PROVIDER: S-EPMC7481223 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Transgenerational inheritance of impaired larval T cell development in zebrafish.

Iwanami Norimasa N Lawir Divine-Fondzenyuy DF Sikora Katarzyna K O Meara Connor C Takeshita Kohei K Schorpp Michael M Boehm Thomas T

Nature communications 20200909 1

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 a ...[more]

PMID: 32908148

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Project description: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 next generation. Although this phenomenon is well described in yeast and plants, and in some invertebrates, such as the D. melanogaster and C. elegans, the evidence for transgenerational inheritance in vertebrates is scarce. Among the mechanisms that are known or suspected to be involved in mediating the propagation of epigenetic information to subsequent generations, the process of enzymatic DNA methylation is of particular interest. During DNA replication, the methylation pattern of the parental strand is faithfully copied onto the daughter strand by the maintenance methylase DNMT1, although methylation patterns can be changed through the action of de novo methylases and mechanisms of active and passive demethylation. In the context of epigenetic inheritance, the induction of aberrant methylation patterns 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. Surprisingly, homozygous mutants present with an essentially normal phenotype, with the exception of drastically impaired lymphopoiesis, affecting both larval and adult phases of T cell development. Male but not female mutants are fertile. The phenotype of impaired larval (but not adult) T cell development is transmitted to subsequent generations by about 50% of fish that are genotypically wildtype. Whole genome bisulfite sequencing of sperm DNA of transmitting and non-transmitting males identified about 200 differentially methylated regions, including hypermethylated sites associated with runx3 and rptor genes. Knock-down of these two genes leads to impaired larval T cell development. Our results raise the possibility of an epigenetic origin of certain immunodeficiency syndromes in animals and humans.

Project description:The aryl hydrocarbon receptor nuclear translocator (ARNT) is a basic helix-loop-helix-PAS heterodimeric transcription factor that dimerizes with other basic helix-loop-helix-PAS proteins to mediate biological responses. The function of ARNT2 is poorly understood. Here we provide an initial characterization of the zebrafish arnt2 null (arnt2(-/-)) mutant to identify functions of Arnt2 during development. Arnt2(-/-) mutant zebrafish develop normally until 120 hours postfertilization (hpf ) when morphological changes and functional deficits occur. The C-start escape response initiated by either touch or startle stimuli is absent in the mutants. Brain ventricle size is markedly increased at 120 hpf. Heart ventricles are enlarged, with decreased ventricle wall thickness. A cardiac arrhythmia, characterized by missing beats, is also observed in the mutants. This is associated with bradycardia in arnt2(-/-) larvae. Dilated liver sinusoids merge abnormally to form an extensive, labyrinth-like network of vascular channels. External appearance of arnt2(-/-) larvae at 120 hpf is indistinguishable from wild type except that the swim bladder is not inflated. The arnt2(-/-) mutants are not debilitated when phenotypic effects are first detected at 120 hpf that culminate in mortality, 4 days later around 216 hpf. Gross morphological assessment of the development of forebrain, midbrain, and hindbrain regions, neuromasts and Mauthner neurons, inner ear semicircular canals and otoliths, primary motor neurons, trigeminal ganglia, and trunk skeletal muscles, before or when the arnt2(-/-) phenotype was observed, failed to demonstrate a difference from wild type. The only effect in arnt2(-/-) larvae that occurred before 120 hpf was a decrease in expression of sim1, an Arnt2 dimerization partner, in the hypothalamus and ventral thalamus at 72 hpf. Further research is needed to determine if the primary functions of Arnt2 occur during the larval stage, when the phenotype is observed, or earlier in development.

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Transgenerational inheritance of impaired larval T cell development in zebrafish.

Publications

Transgenerational inheritance of impaired larval T cell development in zebrafish.

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