H3K18ac Primes Mesendodermal Differentiation upon Nodal Signaling

Area of Science:

• Developmental Biology
• Epigenetics
• Cell Signaling

Background:

• Cellular responses to transforming growth factor β (TGF-β) are context-dependent.
• The interplay between TGF-β/nodal signaling and the epigenome in mesendodermal differentiation requires further elucidation.

Purpose of the Study:

• To investigate the crosstalk between TGF-β/nodal signaling and the epigenome during mesendodermal differentiation.
• To identify key epigenetic regulators and their mechanisms in mediating cell context-dependent TGF-β responses.

Main Methods:

• Utilized embryoid bodies (EBs) and embryonic stem cells (ESCs) models.
• Performed chromatin immunoprecipitation (ChIP) assays to assess protein binding and histone modifications.
• Employed ATAC-sequencing (ATAC-seq) to analyze chromatin accessibility.

Main Results:

• Mesendodermal gene expression in EBs, but not ESCs, depends on TRIM33 and nodal signaling.
• TRIM33 recruitment to mesendodermal genes in EBs is facilitated by H3K18ac marks.
• HDAC1 inhibits TRIM33 recruitment, while p300 enhances it by depositing H3K18ac.
• TRIM33 maintains chromatin accessibility at mesendodermal gene regulatory regions, priming them for activation.

Conclusions:

• HDAC1 and p300 are critical mediators linking the epigenome, TRIM33, and cell context-dependent nodal signaling in mesendodermal differentiation.
• TRIM33 plays a key role in establishing an accessible chromatin state for mesendodermal gene activation.