Distinct Roles for SETα and SETβ in Early Cell Fate Decisions

Abstract

SET, the nuclear proto-oncogene, is primarily expressed as SET in embryonic stem cells. Upon pluripotency exit, a transcriptional switch driven by alternative promoters causes SET{beta} to largely replace SET expression. Functional distinctions between the two isoforms have been difficult to ascertain, partly due to the redundancy between SET and SET{beta} in their protein structure and activity. In this study, we use embryonic stem cells (ESCs) with inducible SET isoform-specific expression to investigate the differences between both SET isoforms. Time-course RNA-seq analyses in SET-KO backgrounds as well as isoform-specific ChIP-seq experiments reveal regulatory functions for SET and SET{beta}. Despite sharing many binding sites and binding partners, SET has unique regulatory functions on its target genes, while SET{beta} downregulates FGF4. As KLF5 specifically regulates SET, this implicates SET isoform switching at the KLF5/FGF signalling axis during primitive endoderm specification. Together, we propose a model of how distinct roles of SET and SET{beta} may regulate cell identity in the early blastocyst.