Spatiotemporal dynamics of histone H3K27 demethylase during development

Spatiotemporal gene expression is fundamental to cellular identity and function, ensuring proper development and tissue homeostasis. Histone modifications, such as H3K4 methylation (associated with active transcription) and H3K27 methylation (linked to repression), act as molecular switches that fine-tune gene expression. However, it remains largely unclear whether and how the histone modifying enzymes are regulated during normal development. In Drosophila, Utx, the sole H3K27 demethylase, plays a crucial role in removing di- and trimethylation marks on H3K27 across the genome. Here, we provide the first evidence that Utx transcription is dynamically regulated, with its regulatory elements exhibiting distinct temporal and spatial activity throughout development. Despite this variability at the transcriptional level, Utx protein is ubiquitously expressed and relatively stable. We found that the regulatory elements of Utx are highly active during embryogenesis but become largely inactivated in wing, eye and leg progenitor tissues during larval and pupal stages. Intriguingly, these regulatory elements are persistently active in the brain into adulthood. Disrupting this dynamic regulation activates a surveillance mechanism that limits excess Utx from translocating into the nucleus, thereby ensuring optimal nuclear protein levels. Moreover, while the Jumonji C (JmjC) demethylase activity of Utx is essential for Drosophila viability, we also discovered that the integrity of this domain is crucial for Utx protein expression. Our findings uncover a previously unrecognized aspect of Utx regulation, highlighting how precise control of its expression and localization safeguards developmental processes and maintains epigenetic stability.