Specific chromatin marks keep master regulators of differentiation silent, yet poised for activation by extracellular signals. We report that nodal TGF-β signals use the poised histone mark H3K9me3 to trigger differentiation of mammalian embryonic stem cells. Nodal receptors induce the formation of companion Smad4-Smad2/3 and TRIM33-Smad2/3 complexes. TRIM33-Smad2/3 binds the histone marks H3K9me3 and K18ac on the promoters of mesendoderm regulators Gsc and Mixl1. Binding is through the PHD-Bromo cassette of TRIM33. In the crystal structure of this cassette bound to histone H3 peptides, PHD recognizes K9me3 and Bromo an adjacent K18ac. Binding of TRIM33-Smad2/3 to H3K9me3 displaces the chromatin compacting factor HP1γ and makes nodal response elements accessible to Smad4-Smad2/3 for Pol II recruitment. In turn, Smad4 increases K18 acetylation to augment TRIM33-Smad2/3 binding. Thus, nodal cues use the H3K9me3 mark as a platform to switch master regulators of stem cell differentiation from the poised to the active state.
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