SETD3 regulates endoderm differentiation of mouse embryonic stem cells through canonical Wnt signaling pathway.

Date

2024-02-29

Author

Alganatay, Ceren
Balbasi, Emre
Tuncbag, Nurcan
Sezginmert, Dersu
Terzi Çizmecioğlu, Nihal

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With self- renewal and pluripotency features, embryonic stem cells (ESCs) provide an invaluable tool to investigate early cell fate decisions. Pluripotency exit and lin-eage commitment depend on precise regulation of gene expression that requires coordination between transcription (TF) and chromatin factors in response to vari-ous signaling pathways. SET domain- containing 3 (SETD3) is a methyltransferase that can modify histones in the nucleus and actin in the cytoplasm. Through an shRNA screen, we previously identified SETD3 as an important factor in the meso/endodermal lineage commitment of mouse ESCs (mESC). In this study, we identi-fied SETD3- dependent transcriptomic changes during endoderm differentiation of mESCs using time- course RNA- seq analysis. We found that SETD3 is involved in the timely activation of the endoderm- related gene network. The canonical Wnt signaling pathway was one of the markedly altered signaling pathways in the ab-sence of SETD3. The assessment of Wnt transcriptional activity revealed a signifi-cant reduction in Setd3- deleted (setd3∆) mESCs coincident with a decrease in the nuclear pool of the key TF β- catenin level, though no change was observed in its mRNA or total protein level. Furthermore, a proximity ligation assay (PLA) found an interaction between SETD3 and β- catenin. We were able to rescue the differ-entiation defect by stably re- expressing SETD3 or activating the canonical Wnt signaling pathway by changing mESC culture conditions. Our results suggest that alterations in the canonical Wnt pathway activity and subcellular localization of β- catenin might contribute to the endoderm differentiation defect of setd3∆ mESCs.

Subject Keywords

beta-catenin, canonical, definitive endoderm, mESCs, mouse embryonic stem cells, SET domain-containing 3 protein, Wnt pathway

URI

https://hdl.handle.net/11511/108589

Collections

Department of Biology, Article