Functional redundancy between UTY and UTX in regulating the localization of transcription factors involved in pluripotency [ATAC-seq]

The Y chromosome retains a limited number of protein-coding genes, yet their biological significance remains poorly understood. Here, we find UTY, a Y-linked homolog of the histone demethylase UTX, plays an essential regulator of pluripotency in human embryonic stem cells. Despite its low expression and weak enzymatic activity, UTY co-localizes with UTX at active cis-regulatory elements and contributes to the regulation of core pluripotency genes such as NODAL and LEFTY. Through genome-wide occupancy and transcriptome analyses of knockout cell lines, we show that UTY and UTX function redundantly to maintain proper localization of key transcription factors including OCT4 and SOX2. Dual loss of UTY and UTX leads to their mislocalization, widespread transcriptional dysregulation, and loss of pluripotency, without changes in H3K27 methylation. Instead, these effects are associated with changes in histone acetylation and altered chromatin accessibility, likely driven by recruitment of ATP-dependent chromatin remodelers, pointing to a non-enzymatic mechanism. Our findings uncover a novel role for UTY in stabilizing transcription factor binding and maintaining cell identity, demonstrating that even the evolutionarily compact Y chromosome retains critical regulatory functions in early human development.