Distinct roles for SETα and SETβ in early cell fate decisions

Area of Science:

• Developmental Biology
• Cellular and Molecular Biology
• Epigenetics

Background:

• SET is a nuclear proto-oncogene with two main isoforms, SETα and SETβ.
• SETα is dominant in embryonic stem cells (ESCs), while SETβ replaces it upon pluripotency exit.
• Functional differences between SETα and SETβ are unclear due to structural and activity redundancy.

Purpose of the Study:

• To investigate the distinct regulatory functions of SETα and SETβ isoforms.
• To elucidate the roles of SET isoforms in early cell fate decisions.
• To understand the SET isoform switch mechanism during pluripotency exit.

Main Methods:

• Utilized ESCs with inducible SET isoform-specific expression.
• Performed time-course RNA-sequencing in SET-knockout backgrounds.
• Conducted isoform-specific chromatin immunoprecipitation followed by sequencing (ChIP-seq).

Main Results:

• Identified unique regulatory functions for SETα and SETβ despite shared binding sites and partners.
• Demonstrated that SETα has distinct regulatory functions on its target genes.
• Showed that SETβ specifically downregulates FGF4.
• Found that KLF5 specifically regulates SETα, linking SET isoform switching to the KLF5/FGF signaling axis.

Conclusions:

• SETα and SETβ possess distinct regulatory roles impacting cell identity.
• SET isoform switching, particularly involving SETα and FGF4 regulation by SETβ, is crucial for primitive endoderm specification.
• A model is proposed where distinct SET isoform functions regulate early blastocyst cell identity.