H3K18ac Primes Mesendodermal Differentiation upon Nodal Signaling

Cellular responses to transforming growth factor β (TGF-β) depend on cell context. Here, we explored how TGF-β/nodal signaling crosstalks with the epigenome to promote mesendodermal differentiation. We find that expression of a group of mesendodermal genes depends on both TRIM33 and nodal signaling in embryoid bodies (EBs) but not in embryonic stem cells (ESCs). Only in EBs, TRIM33 binds these genes in the presence of expanded H3K18ac marks. Furthermore, the H3K18ac landscape at mesendodermal genes promotes TRIM33 recruitment. We reveal that HDAC1 binds to active gene promoters and interferes with TRIM33 recruitment to mesendodermal gene promoters. However, the TRIM33-interacting protein p300 deposits H3K18ac and further enhances TRIM33 recruitment. ATAC-seq data demonstrate that TRIM33 primes mesendodermal genes for activation by maintaining chromatin accessibility at their regulatory regions. Altogether, our study suggests that HDAC1 and p300 are key factors linking the epigenome through TRIM33 to the cell context-dependent nodal response during mesendodermal differentiation. •The H3K18ac landscape changes at gene promoters during mesendodermal differentiation•Histone acetylation facilitates TRIM33 recruitment to the chromatin•HDAC1 and p300 are the key factors for nodal signaling crosstalk with epigenome•Chromatin accessibility at mesendodermal genes depends on TRIM33 Xi and colleagues explored how nodal signaling crosstalks with epigenome to specifically promote mesendodermal differentiation. They showed that TRIM33 specifically regulates the expression of a group of mesendodermal genes upon nodal signaling by maintaining the H3K18ac mark, and that HDAC1 and p300 are the key factors linking epigenome to the cell context-dependent nature of nodal responses during mesendodermal differentiation.