Setdb2 restricts dorsal organizer territory and regulates left-right asymmetry through suppressing fgf8 activity

Xu, P.F., Zhu, K.Y., Jin, Y., Chen, Y., Sun, X.J., Deng, M., Chen, S.J., Chen, Z., and Liu, T.X.
Proceedings of the National Academy of Sciences of the United States of America   107(6): 2521-2526 (Journal)
Registered Authors
Chen, Yi, Chen, Zhu, Deng, Min, Jin, Yi, Liu, Ting Xi, Sun, Xiao-Jian, Xu, Peng-Fei, Zhu, Kang-Yong
set domain, histone methylation, epigenetics, embryonic development, zebrafish
MeSH Terms
  • Amino Acid Sequence
  • Animals
  • Body Patterning/genetics*
  • Embryo, Nonmammalian/embryology
  • Embryo, Nonmammalian/metabolism*
  • Fibroblast Growth Factor 8/genetics*
  • Gene Expression Regulation, Developmental
  • Gene Knockdown Techniques
  • Glycoproteins/genetics
  • Goosecoid Protein/genetics
  • Histone-Lysine N-Methyltransferase/genetics*
  • Homeodomain Proteins/genetics
  • In Situ Hybridization
  • Intercellular Signaling Peptides and Proteins/genetics
  • Molecular Sequence Data
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • Sequence Homology, Amino Acid
  • Transcription Factors/genetics
  • Zebrafish Proteins/genetics*
20133783 Full text @ Proc. Natl. Acad. Sci. USA
Dorsal organizer formation is one of the most critical steps in early embryonic development. Several genes and signaling pathways that positively regulate the dorsal organizer development have been identified; however, little is known about the factor(s) that negatively regulates the organizer formation. Here, we show that Setdb2, a SET domain-containing protein possessing potential histone H3K9 methyltransferase activity, restricts dorsal organizer development and regulates left-right asymmetry by suppressing fibroblast growth factor 8 (fgf8) expression. Knockdown of Setdb2 results in a massive expansion of dorsal organizer markers floating head (flh), goosecoid (gsc), and chordin (chd), as well as a significant increase of fgf8, but not fgf4 mRNAs. Consequently, disrupted midline patterning and resultant randomization of left-right asymmetry are observed in Setdb2-deficient embryos. These characteristic changes induced by Setdb2 deficiency can be nearly corrected by either overexpression of a dominant-negative fgf receptor or knockdown of fgf8, suggesting an essential role for Setdb2-Fgf8 signaling in restricting dorsal organizer territory and regulating left-right asymmetry. These results provide unique evidence that a SET domain-containing protein potentially involved in the epigenetic control negatively regulates dorsal organizer formation during early embryonic development.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes