H3K18ac Primes Mesendodermal Differentiation upon Nodal Signaling

Stem Cell Reports. 2019 Oct 8;13(4):642-656. doi: 10.1016/j.stemcr.2019.08.016. Epub 2019 Sep 26.


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.

Keywords: TRIM33; chromatin accessibility; embryonic stem cells; histone acetylation; mesendodermal differentiation; nodal signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Cell Differentiation* / genetics
  • Chromatin / genetics
  • Chromatin / metabolism
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism
  • Gene Expression Regulation, Developmental
  • Histones / metabolism*
  • Humans
  • Mesoderm / cytology*
  • Mesoderm / metabolism*
  • Nodal Protein / metabolism*
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Transport
  • Signal Transduction*
  • Smad2 Protein / metabolism
  • Smad3 Protein / metabolism
  • Transcription Factors / metabolism
  • p300-CBP Transcription Factors / metabolism


  • Chromatin
  • Histones
  • NODAL protein, human
  • Nodal Protein
  • Smad2 Protein
  • Smad3 Protein
  • TRIM33 protein, human
  • Transcription Factors
  • p300-CBP Transcription Factors