Research ArticleGene Regulation

Nodal Signaling Recruits the Histone Demethylase Jmjd3 to Counteract Polycomb-Mediated Repression at Target Genes

Sci. Signal.  22 Jun 2010:
Vol. 3, Issue 127, pp. ra48
DOI: 10.1126/scisignal.2000841

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Regulatory Two-Step

During the development of metazoans, lineage-specific patterns of gene expression that become stably maintained across many cell generations are established in response to transient intercellular signals. One such signal is the transforming growth factor–β (TGF-β)–related ligand, Nodal, which is required for the formation of mesoderm and endoderm and for body patterning. The established gene expression programs are still responsive to further developmental cues, and this transcriptional plasticity arises due to epigenetic regulation at the level of chromatin. Trimethylation of Lys27 (K27) of histone H3 (H3K27me3) is mediated by Polycomb, which results in repression of gene expression. Histone demethylases, such as Jmjd3, target H3K27me3, which renders Polycomb-mediated repression highly dynamic; however, how the activity of Polycomb is linked to developmental, intercellular signaling pathways is unclear. Dahle et al. showed that the expression of Nodal, which depends on Nodal activity, was repressed by Polycomb-mediated deposition of H3K27me3 and that Nodal signaling, through the proteins Smad2 and Smad3 (Smads2/3), recruited Jmjd3 to the Nodal locus to counteract the effects of Polycomb. In the absence of Polycomb, the expression of Nodal and another Nodal target, Brachyury, was independent of Nodal signaling. Together, these findings suggest how transcriptional plasticity can arise through cooperation between the epigenetic machinery and developmental signaling pathways.

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