期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 6, 页码 2521-2526出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0914396107
关键词
set domain; histone methylation; epigenetics; embryonic development; zebrafish
资金
- National Basic Research Program of China [2007CB947003]
- National Natural Science Foundation of China [30525019, 30830047]
- Science and Technology Commission of Shanghai Municipality [09XD1404700]
- National High Tech Program for Biotechnology (863) [2006AA02A405]
- Chinese National Key Basic Research Project (973) [2010CB529200]
- Shanghai Municipal Education Commission [Y0201]
- Grant for Innovation Group of the National Natural Science Foundation of China [30821063]
- Shanghai Municipal Commission for Science and Technology [06DZ2202, 07DZ05908, 08DZ2200100]
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.
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