Identification of Distinct Loci for De Novo DNA Methylation by DNMT3A and DNMT3B During Mammalian Development

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Jun 26

PMID 32581223

Citations 35

Authors

Masaki Yagi

Mio Kabata

Akito Tanaka

Tomoyo Ukai

Sho Ohta

Kazuhiko Nakabayashi

Masahito Shimizu

Kenichiro Hata

Alexander Meissner

Takuya Yamamoto

Yasuhiro Yamada

Affiliations

Soon will be listed here.

Abstract

De novo establishment of DNA methylation is accomplished by DNMT3A and DNMT3B. Here, we analyze de novo DNA methylation in mouse embryonic fibroblasts (2i-MEFs) derived from DNA-hypomethylated 2i/L ES cells with genetic ablation of Dnmt3a or Dnmt3b. We identify 355 and 333 uniquely unmethylated genes in Dnmt3a and Dnmt3b knockout (KO) 2i-MEFs, respectively. We find that Dnmt3a is exclusively required for de novo methylation at both TSS regions and gene bodies of Polycomb group (PcG) target developmental genes, while Dnmt3b has a dominant role on the X chromosome. Consistent with this, tissue-specific DNA methylation at PcG target genes is substantially reduced in Dnmt3a KO embryos. Finally, we find that human patients with DNMT3 mutations exhibit reduced DNA methylation at regions that are hypomethylated in Dnmt3 KO 2i-MEFs. In conclusion, here we report a set of unique de novo DNA methylation target sites for both DNMT3 enzymes during mammalian development that overlap with hypomethylated sites in human patients.

Citing Articles

Tissue-specific roles of de novo DNA methyltransferases.

Toth D, Szeri F, Ashaber M, Muazu M, Szekvolgyi L, Aranyi T Epigenetics Chromatin. 2025; 18(1):5.

PMID: 39819598 PMC: 11740433. DOI: 10.1186/s13072-024-00566-2.

Epigenetic Mechanisms in Aging: Extrinsic Factors and Gut Microbiome.

Borrego-Ruiz A, Borrego J Genes (Basel). 2025; 15(12.

PMID: 39766866 PMC: 11675900. DOI: 10.3390/genes15121599.

Multifaceted role of CTCF in X-chromosome inactivation.

Bammidi L, Gayen S Chromosoma. 2024; 133(4):217-231.

PMID: 39433641 DOI: 10.1007/s00412-024-00826-w.

The proteomic landscape and temporal dynamics of mammalian gastruloid development.

Garge R, Lynch V, Fields R, Casadei S, Best S, Stone J bioRxiv. 2024; .

PMID: 39282277 PMC: 11398484. DOI: 10.1101/2024.09.05.609098.

Mammalian genome research resources available from the National BioResource Project in Japan.

Mizuno-Iijima S, Kawamoto S, Asano M, Mashimo T, Wakana S, Nakamura K Mamm Genome. 2024; 35(4):497-523.

PMID: 39261329 PMC: 11522087. DOI: 10.1007/s00335-024-10063-2.

References

Smith Z, Meissner A . DNA methylation: roles in mammalian development. Nat Rev Genet. 2013; 14(3):204-20. DOI: 10.1038/nrg3354. View

Bird A . DNA methylation patterns and epigenetic memory. Genes Dev. 2002; 16(1):6-21. DOI: 10.1101/gad.947102. View

Jaenisch R, Bird A . Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003; 33 Suppl:245-54. DOI: 10.1038/ng1089. View

Jackson M, Krassowska A, Gilbert N, Chevassut T, Forrester L, Ansell J . Severe global DNA hypomethylation blocks differentiation and induces histone hyperacetylation in embryonic stem cells. Mol Cell Biol. 2004; 24(20):8862-71. PMC: 517875. DOI: 10.1128/MCB.24.20.8862-8871.2004. View

Okano M, BELL D, Haber D, Li E . DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999; 99(3):247-57. DOI: 10.1016/s0092-8674(00)81656-6. View

Li E, Bestor T, Jaenisch R . Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell. 1992; 69(6):915-26. DOI: 10.1016/0092-8674(92)90611-f. View

Jin B, Tao Q, Peng J, Soo H, Wu W, Ying J . DNA methyltransferase 3B (DNMT3B) mutations in ICF syndrome lead to altered epigenetic modifications and aberrant expression of genes regulating development, neurogenesis and immune function. Hum Mol Genet. 2007; 17(5):690-709. DOI: 10.1093/hmg/ddm341. View

Shah M, Licht J . DNMT3A mutations in acute myeloid leukemia. Nat Genet. 2011; 43(4):289-90. DOI: 10.1038/ng0411-289. View

Smith Z, Chan M, Mikkelsen T, Gu H, Gnirke A, Regev A . A unique regulatory phase of DNA methylation in the early mammalian embryo. Nature. 2012; 484(7394):339-44. PMC: 3331945. DOI: 10.1038/nature10960. View

10.

Smith Z, Shi J, Gu H, Donaghey J, Clement K, Cacchiarelli D . Epigenetic restriction of extraembryonic lineages mirrors the somatic transition to cancer. Nature. 2017; 549(7673):543-547. PMC: 5789792. DOI: 10.1038/nature23891. View

11.

Bourchis D, Xu G, Lin C, Bollman B, Bestor T . Dnmt3L and the establishment of maternal genomic imprints. Science. 2001; 294(5551):2536-9. DOI: 10.1126/science.1065848. View

12.

Hata K, Okano M, Lei H, Li E . Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. Development. 2002; 129(8):1983-93. DOI: 10.1242/dev.129.8.1983. View

13.

Kaneda M, Okano M, Hata K, Sado T, Tsujimoto N, Li E . Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature. 2004; 429(6994):900-3. DOI: 10.1038/nature02633. View

14.

Baubec T, Colombo D, Wirbelauer C, Schmidt J, Burger L, Krebs A . Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature. 2015; 520(7546):243-7. DOI: 10.1038/nature14176. View

15.

Manzo M, Wirz J, Ambrosi C, Villasenor R, Roschitzki B, Baubec T . Isoform-specific localization of DNMT3A regulates DNA methylation fidelity at bivalent CpG islands. EMBO J. 2017; 36(23):3421-3434. PMC: 5709737. DOI: 10.15252/embj.201797038. View

16.

Yagi M, Kishigami S, Tanaka A, Semi K, Mizutani E, Wakayama S . Derivation of ground-state female ES cells maintaining gamete-derived DNA methylation. Nature. 2017; 548(7666):224-227. DOI: 10.1038/nature23286. View

17.

Hackett J, Surani M . Regulatory principles of pluripotency: from the ground state up. Cell Stem Cell. 2014; 15(4):416-430. DOI: 10.1016/j.stem.2014.09.015. View

18.

Shirane K, Kurimoto K, Yabuta Y, Yamaji M, Satoh J, Ito S . Global Landscape and Regulatory Principles of DNA Methylation Reprogramming for Germ Cell Specification by Mouse Pluripotent Stem Cells. Dev Cell. 2016; 39(1):87-103. DOI: 10.1016/j.devcel.2016.08.008. View

19.

Gendrel A, Apedaile A, Coker H, Termanis A, Zvetkova I, Godwin J . Smchd1-dependent and -independent pathways determine developmental dynamics of CpG island methylation on the inactive X chromosome. Dev Cell. 2012; 23(2):265-79. PMC: 3437444. DOI: 10.1016/j.devcel.2012.06.011. View

20.

Liao J, Karnik R, Gu H, Ziller M, Clement K, Tsankov A . Targeted disruption of DNMT1, DNMT3A and DNMT3B in human embryonic stem cells. Nat Genet. 2015; 47(5):469-78. PMC: 4414868. DOI: 10.1038/ng.3258. View