biostudies-literatureShi BNCI NIH HHSNIH HHSNIGMS NIH HHS726-731https://www.ebi.ac.uk/biostudies/studies/S-EPMC9008583biostudies-literatureUnknown597(7878)UTX (also known as KDM6A) encodes a histone H3K27 demethylase and is an important tumour suppressor that is frequently mutated in human cancers¹. However, as the demethylase activity of UTX is often dispensable for mediating tumour suppression and developmental regulation^2-8, the underlying molecular activity of UTX remains unknown. Here we show that phase separation of UTX underlies its chromatin-regulatory activity in tumour suppression. A core intrinsically disordered region (cIDR) of UTX forms phase-separated liquid condensates, and cIDR loss caused by the most frequent cancer mutation of UTX is mainly responsible for abolishing tumour suppression. Deletion, mutagenesis and replacement assays of the intrinsically disordered region demonstrate a critical role of UTNatureUTX condensation underlies its tumour-suppressive activity.PMC9008583P41 GM103540R35 GM133712S10 OD025156R21 CA257936S10 OD016446OD016446P30 CA044579Dimoff DJarrard WJiang HDigman MAUlman AZhao YLi WLe JPPalomba FShi BHu JGratton EWang ZZang CJu RSong YfalseUTX condensation underlies its tumour-suppressive activity.UTX (also known as KDM6A) encodes a histone H3K27 demethylase and is an important tumour suppressor that is frequently mutated in human cancers¹. However, as the demethylase activity of UTX is often dispensable for mediating tumour suppression and developmental regulation^2-8, the underlying molecular activity of UTX remains unknown. Here we show that phase separation of UTX underlies its chromatin-regulatory activity in tumour suppression. A core intrinsically disordered region (cIDR) of UTX forms phase-separated liquid condensates, and cIDR loss caused by the most frequent cancer mutation of UTX is mainly responsible for abolishing tumour suppression. Deletion, mutagenesis and replacement assays of the intrinsically disordered region demonstrate a critical role of UT2021-01-01T00:00:00Z2021 Sep2026-04-08T10:15:54.315Z2025-02-19T00:38:10.426ZS-EPMC90085833452671610.1038/s41586-021-03903-7