Uterine fibroids, or uterine leiomyoma (UL), are benign tumours of the uterine wall. Up to 30% of women will develop symptomatic UL, with symptoms including pain, heavy menstruation and reduced fertility, in some cases requiring surgery. Previous work identified mutually exclusive mutations in MED12 and FH or activation of HMGA2 as genetic drivers of UL. To further dissect the genetic background of these tumours, Berta et al. performed multi-omics analysis on tumour samples and paired normal myometrium from 728 patients with UL. Their dataset identified a subgroup of tumours with mutations in or aberrant expression of genes encoding subunits of the SRCAP complex, an epigenetic remodeller that regulates chromatin structure by depositing the histone variant H2A.Z onto DNA. They found that loss-of-function mutations in two of these genes (YEATS4 and ZNHIT1) strongly associate with UL in an independent study using data from the UK Biobank. Chromatin immunoprecipitation with sequencing (ChIP–seq) data showed tumours with SRCAP alterations have a genome-wide reduction in H2A.Z–chromatin binding compared with normal myometrium. The investigation of chromatin organization showed that areas of open chromatin in YEATS4-mutated tumours were enriched for bivalent transcription start sites, with corresponding changes in the expression of genes, many associated with development and cell differentiation. Overall, these data describe a novel mechanism of tumorigenesis induced by deficiencies in H2A.Z deposition and extensive alterations in chromatin configuration.