Zfp462 Regulates the Pluripotency of Embryonic Stem Cells by Cooperating with the Core Transcriptional Network

Zinc finger PBX1-interacting protein (Zfp462/Zfpip), a vertebrate-specific C2H2-type transcription factor, plays an essential role in early embryogenesis and the maintenance of embryonic stem cell (ESC) pluripotency. While previous studies have largely focused on its repressive functions, its potential role in transcriptional activation has remained unclear. In this study, we demonstrate that Zfp462 knockout (KO) impairs ESC self-renewal and disrupts the expression of pluripotency-associated and developmental genes. Luciferase reporter assays showed that Zfp462 overexpression increased Oct4 (also known as Pou5f1 ) promoter activity, whereas Zfp462 KO reduced its activity, supporting a role for Zfp462 in transcriptional activation. Integrative multiomics analyses reveal that Zfp462 is functionally integrated into the ESC core pluripotency module and cooperates with Oct4, Sox2, and Nanog to activate pluripotency-associated genes. Together, these findings reveal a critical role for Zfp462 in ESC pluripotency and establish it as a novel regulator within the pluripotency gene regulatory network.