Abstract
Embryonic cell fate specification and axis patterning requires integration of several signaling pathways that orchestrate region-specific gene expression. The transcription factor signal transducer and activator of transcription 3 (Stat3) plays important roles during early development, but it is unclear how Stat3 is activated. Here, using Xenopus as a model, we analyzed the post-translational regulation and functional consequences of Stat3 activation in dorsoventral axis patterning. We show that Stat3 phosphorylation, lysine methylation, and transcriptional activity increase before gastrulation and induce ventral mesoderm formation. Down syndrome critical region gene 6 (DSCR6), a RIPPLY family member that induces dorsal mesoderm by releasing repressive polycomb group proteins from chromatin, bound to the Stat3 C-terminal region and antagonized its transcriptional and ventralizing activities by interfering with its lysine methylation. Enhancer of zeste 2 polycomb-repressive complex 2 subunit (Ezh2) also bound to this region; however, its methyltransferase activity was required for Stat3 methylation and activation. Loss of Ezh2 resulted in dorsalization of ventral mesoderm and formation of a secondary axis. Furthermore, interference with Ezh2 phosphorylation also prevented Stat3 lysine methylation and transcriptional activity. Thus, inhibition of either Ezh2 phosphorylation or Stat3 lysine methylation compensated for the absence of DSCR6 function. These results reveal that DSCR6 and Ezh2 critically and post-translationally regulate Stat3 transcriptional activity. Ezh2 promotes Stat3 activation in ventral mesoderm formation independently of epigenetic regulation, whereas DSCR6 specifies dorsal fate by counteracting this ventralizing activity. This antagonism helps pattern the mesoderm along the dorsoventral axis, representing a critical facet of cell identity regulation during development.
Highlights
Embryonic cell fate specification and axis patterning requires integration of several signaling pathways that orchestrate region-specific gene expression
Among different ventralizing factors tested, we found that Down syndrome critical region gene 6 (DSCR6) biochemically interacted with signal transducer and activator of transcription 3 (Stat3), whose activation was shown to inhibit dorsal mesoderm formation [27]
The results showed that the expression of Ezh2 and Dscr6 remained unchanged (Fig. S5), this suggests that Stat3 does not feedback to regulate Ezh2 or Dscr6 in mesoderm patterning
Summary
Ezh promotes Stat activation in ventral mesoderm formation independently of epigenetic regulation, whereas DSCR6 specifies dorsal fate by counteracting this ventralizing activity This antagonism helps pattern the mesoderm along the dorsoventral axis, representing a critical facet of cell identity regulation during development. Specified after fertilization as a result of inductive interactions that involve different critical signaling pathways and transcription factors [1] During gastrulation, these cells are further patterned along the dorsoventral (DV) axis in a regionally specific manner to generate different types of mesoderm tissues of the future embryo. In Xenopus, DSCR6 physically and functionally interacts with polycomb group (PcG) proteins to prevent their repressive activity on dorsal mesoderm gene expression [8] This suggests that the interaction between PcG proteins and their antagonistic factors plays an important role in DV patterning during early development. This work reveals a critical nonepigenetic role of DSCR6 and Ezh in the post-translational control of embryonic axis patterning
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