Uracil-DNA Glycosylase is Involved in DNA Demethylation and Required for Embryonic Development in the Zebrafish Embryo

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2014 Apr 18

PMID 24739389

Citations 12

Authors

Di Wu

Luxi Chen

Qingrui Sun

Xiaotong Wu

Shunji Jia

Anming Meng

Affiliations

Soon will be listed here.

Abstract

Uracil-DNA glycosylase (Ung) is a component of the base excision repair process and has the ability to remove uracil from U:G mispairs in DNA. However, its implications in development of vertebrate embryos are poorly understood. In this study, we found that zebrafish uracil-DNA glycosylase a (Unga) is maternally expressed at high levels and accumulated in nuclei during cleavage and blastulation periods. Knockdown of unga in zebrafish embryos causes an increase of the global DNA methylation level concomitantly with a reduction of overall transcriptional activity in the nucleus, ultimately resulting in embryonic lethality during segmentation period. Conversely, unga overexpression is sufficient to reduce the global DNA methylation level, to increase H3K4me3 and H3K27me3 marks, and to activate genome transcription. Furthermore, overexpression of unga(D132A) mRNA, encoding a mutant Unga without DNA glycosylase activity, does not affect global DNA methylation level, indicating that its involvement in DNA demethylation is dependent on its glycosylase activity. These results together suggest that Unga is implicated in postfertilization genomic DNA demethylation, zygotic gene transcription, and normal embryonic development in zebrafish.

Citing Articles

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References

Parikh S, Mol C, Slupphaug G, Bharati S, Krokan H, Tainer J . Base excision repair initiation revealed by crystal structures and binding kinetics of human uracil-DNA glycosylase with DNA. EMBO J. 1998; 17(17):5214-26. PMC: 1170849. DOI: 10.1093/emboj/17.17.5214. View

Slupphaug G, Markussen F, Olsen L, Aasland R, Aarsaether N, Bakke O . Nuclear and mitochondrial forms of human uracil-DNA glycosylase are encoded by the same gene. Nucleic Acids Res. 1993; 21(11):2579-84. PMC: 309584. DOI: 10.1093/nar/21.11.2579. View

Okada Y, Yamagata K, Hong K, Wakayama T, Zhang Y . A role for the elongator complex in zygotic paternal genome demethylation. Nature. 2010; 463(7280):554-8. PMC: 2834414. DOI: 10.1038/nature08732. View

Agius F, Kapoor A, Zhu J . Role of the Arabidopsis DNA glycosylase/lyase ROS1 in active DNA demethylation. Proc Natl Acad Sci U S A. 2006; 103(31):11796-801. PMC: 1544249. DOI: 10.1073/pnas.0603563103. View

MacKay A, Mhanni A, McGowan R, Krone P . Immunological detection of changes in genomic DNA methylation during early zebrafish development. Genome. 2007; 50(8):778-85. DOI: 10.1139/g07-055. View

Hajkova P, Ancelin K, Waldmann T, Lacoste N, Lange U, Cesari F . Chromatin dynamics during epigenetic reprogramming in the mouse germ line. Nature. 2008; 452(7189):877-81. PMC: 3847605. DOI: 10.1038/nature06714. View

Jost J, Jost Y . Mechanism of active DNA demethylation during embryonic development and cellular differentiation in vertebrates. Gene. 1995; 157(1-2):265-6. DOI: 10.1016/0378-1119(95)00036-6. View

Cortazar D, Kunz C, Selfridge J, Lettieri T, Saito Y, MacDougall E . Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability. Nature. 2011; 470(7334):419-23. DOI: 10.1038/nature09672. View

Barreto G, Schafer A, Marhold J, Stach D, Swaminathan S, Handa V . Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature. 2007; 445(7128):671-5. DOI: 10.1038/nature05515. View

10.

Roy T, Bhagwat A . Kinetic studies of Escherichia coli AlkB using a new fluorescence-based assay for DNA demethylation. Nucleic Acids Res. 2007; 35(21):e147. PMC: 2175350. DOI: 10.1093/nar/gkm1031. View

11.

Hamm S, Just G, Lacoste N, Moitessier N, Szyf M, Mamer O . On the mechanism of demethylation of 5-methylcytosine in DNA. Bioorg Med Chem Lett. 2007; 18(3):1046-9. DOI: 10.1016/j.bmcl.2007.12.027. View

12.

Gu T, Guo F, Yang H, Wu H, Xu G, Liu W . The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature. 2011; 477(7366):606-10. DOI: 10.1038/nature10443. View

13.

Santos F, Hendrich B, Reik W, Dean W . Dynamic reprogramming of DNA methylation in the early mouse embryo. Dev Biol. 2002; 241(1):172-82. DOI: 10.1006/dbio.2001.0501. View

14.

Lindeman L, Andersen I, Reiner A, Li N, Aanes H, Ostrup O . Prepatterning of developmental gene expression by modified histones before zygotic genome activation. Dev Cell. 2011; 21(6):993-1004. DOI: 10.1016/j.devcel.2011.10.008. View

15.

Jost J, Thiry S, Siegmann M . 5-Methyldeoxycytidine monophosphate deaminase and 5-methylcytidyl-DNA deaminase activities are present in human mature sperm cells. FEBS Lett. 2002; 519(1-3):128-34. DOI: 10.1016/s0014-5793(02)02737-0. View

16.

Jin S, Tsark W, Szabo P, Pfeifer G . Haploid male germ cell- and oocyte-specific Mbd3l1 and Mbd3l2 genes are dispensable for early development, fertility, and zygotic DNA demethylation in the mouse. Dev Dyn. 2008; 237(11):3435-43. PMC: 2673952. DOI: 10.1002/dvdy.21767. View

17.

Santos F, Peat J, Burgess H, Rada C, Reik W, Dean W . Active demethylation in mouse zygotes involves cytosine deamination and base excision repair. Epigenetics Chromatin. 2013; 6(1):39. PMC: 4037648. DOI: 10.1186/1756-8935-6-39. View

18.

Le May N, Fradin D, Iltis I, Bougneres P, Egly J . XPG and XPF endonucleases trigger chromatin looping and DNA demethylation for accurate expression of activated genes. Mol Cell. 2012; 47(4):622-32. DOI: 10.1016/j.molcel.2012.05.050. View

19.

He Y, Li B, Li Z, Liu P, Wang Y, Tang Q . Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science. 2011; 333(6047):1303-7. PMC: 3462231. DOI: 10.1126/science.1210944. View

20.

Guo J, Su Y, Zhong C, Ming G, Song H . Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell. 2011; 145(3):423-34. PMC: 3088758. DOI: 10.1016/j.cell.2011.03.022. View