Transgenerational inheritance of impaired larval T cell development in zebrafish

• Published in: Nature communications Vol. 11; no. 1; pp. 4505 - 13
• Main Authors: Iwanami, Norimasa, Lawir, Divine-Fondzenyuy, Sikora, Katarzyna, O´Meara, Connor, Takeshita, Kohei, Schorpp, Michael, Boehm, Thomas
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.09.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 14; 14/63; 38/23; 38/35; 38/91; 45; 631/136/1455; 631/136/2442; 631/208/176/1988; 631/250; 631/337/176; 64; 64/116; Alleles; Animals; Animals, Genetically Modified; Cell Differentiation - genetics; Core Binding Factor Alpha 3 Subunit - genetics; CpG islands; Danio rerio; Demethylation; Deoxyribonucleic acid; DNA; DNA (Cytosine-5-)-Methyltransferase 1 - genetics; DNA (Cytosine-5-)-Methyltransferase 1 - metabolism; DNA Methylation; DNMT1 protein; Epigenesis, Genetic; Epigenetics; Female; Gametes; Genes, Recessive; Genetics; Heredity; Humanities and Social Sciences; Larva - cytology; Larva - growth & development; Lymphocytes; Lymphocytes T; Lymphopoiesis; Lymphopoiesis - genetics; Male; multidisciplinary; Mutants; Mutation; Phenotypes; Regulatory-Associated Protein of mTOR - genetics; Runx3 protein; Science; Science (multidisciplinary); Sperm; Spermatozoa - metabolism; T-Lymphocytes - physiology; Transmission; Vertebrates; Zebrafish; Zebrafish - genetics; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-18289-9

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. Evidence for transgenerational inheritance of epigenetic information in vertebrates is scarce. Here the authors report that homozygous dnmt1 mutant zebrafish are essentially normal, with the exception of impaired lymphopoiesis, with impaired larval (but not adult) T cell development being transmitted to subsequent generations by genotypically wildtype fish.