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  • Zhang, Xiao-JieUniv Chinese Acad Sci, Peoples R China (author)

Auto-suppression of Tet dioxygenases protects the mouse oocyte genome from oxidative demethylation

  • Article/chapterEnglish2024

Publisher, publication year, extent ...

  • NATURE PORTFOLIO,2024
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:liu-201194
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-201194URI
  • https://doi.org/10.1038/s41594-023-01125-1DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • DNA cytosine methylation plays a vital role in repressing retrotransposons, and such derepression is linked with developmental failure, tumorigenesis and aging. DNA methylation patterns are formed by precisely regulated actions of DNA methylation writers (DNA methyltransferases) and erasers (TET, ten-eleven translocation dioxygenases). However, the mechanisms underlying target-specific oxidation of 5mC by TET dioxygenases remain largely unexplored. Here we show that a large low-complexity domain (LCD), located in the catalytic part of Tet enzymes, negatively regulates the dioxygenase activity. Recombinant Tet3 lacking LCD is shown to be hyperactive in converting 5mC into oxidized species in vitro. Endogenous expression of the hyperactive Tet3 mutant in mouse oocytes results in genome-wide 5mC oxidation. Notably, the occurrence of aberrant 5mC oxidation correlates with a consequent loss of the repressive histone mark H3K9me3 at ERVK retrotransposons. The erosion of both 5mC and H3K9me3 causes ERVK derepression along with upregulation of their neighboring genes, potentially leading to the impairment of oocyte development. These findings suggest that Tet dioxygenases use an intrinsic auto-regulatory mechanism to tightly regulate their enzymatic activity, thus achieving spatiotemporal specificity of methylome reprogramming, and highlight the importance of methylome integrity for development. Here the authors show that TET dioxygenases, the erasers of DNA methylation, use a self-limiting mechanism via their LCD domain to ensure adaptable methylome status and protect the genome from excessive oxidative methylation.

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Added entries (persons, corporate bodies, meetings, titles ...)

  • Han, Bin-BinUniv Chinese Acad Sci, Peoples R China (author)
  • Shao, Zhen-YuUniv Chinese Acad Sci, Peoples R China (author)
  • Yan, RuiUniv Chinese Acad Sci, Peoples R China; Beijing Inst Stem Cell & Regenerat Med, Peoples R China (author)
  • Gao, JuanUniv Chinese Acad Sci, Peoples R China (author)
  • Liu, TingUniv Chinese Acad Sci, Peoples R China; Shanghai Tech Univ, Peoples R China (author)
  • Jin, Zi-YangUniv Chinese Acad Sci, Peoples R China (author)
  • Lai, WeiyiChinese Acad Sci, Peoples R China (author)
  • Xu, Zhi-MeiUniv Chinese Acad Sci, Peoples R China (author)
  • Wang, Chao-HanUniv Chinese Acad Sci, Peoples R China (author)
  • Zhang, FengjuanUniv Chinese Acad Sci, Peoples R China (author)
  • Gu, ChanChangping Lab, Peoples R China (author)
  • Wang, YinChinese Acad Med Sci RU069, Peoples R China; Fudan Univ, Peoples R China (author)
  • Wang, HailinChinese Acad Sci, Peoples R China (author)
  • Walsh, ColumLinköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten,Ulster Univ, North Ireland(Swepub:liu)colwa39 (author)
  • Guo, FanUniv Chinese Acad Sci, Peoples R China; Beijing Inst Stem Cell & Regenerat Med, Peoples R China (author)
  • Xu, Guo-LiangUniv Chinese Acad Sci, Peoples R China; Chinese Acad Med Sci RU069, Peoples R China; Fudan Univ, Peoples R China (author)
  • Du, Ya-RuiUniv Chinese Acad Sci, Peoples R China (author)
  • Univ Chinese Acad Sci, Peoples R ChinaUniv Chinese Acad Sci, Peoples R China; Beijing Inst Stem Cell & Regenerat Med, Peoples R China (creator_code:org_t)

Related titles

  • In:Nature Structural & Molecular Biology: NATURE PORTFOLIO31:11545-99931545-9985

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