Chromatin state origins of uterine leiomyoma

Maritta Räisänen, Eevi Kaasinen, Maija Jäntti, Aurora Taira, Emma Siili, Ralf Bützow, Oskari Heikinheimo, Annukka Pasanen, Auli Karhu, Davide G. Berta, Niko Välimäki and Lauri A. Aaltonen ()
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Maritta Räisänen: University of Helsinki
Eevi Kaasinen: University of Helsinki
Maija Jäntti: University of Helsinki
Aurora Taira: University of Helsinki
Emma Siili: University of Helsinki and Helsinki University Hospital
Ralf Bützow: University of Helsinki
Oskari Heikinheimo: University of Helsinki and Helsinki University Hospital
Annukka Pasanen: University of Helsinki and Helsinki University Hospital
Auli Karhu: University of Helsinki
Davide G. Berta: University of Helsinki
Niko Välimäki: University of Helsinki
Lauri A. Aaltonen: University of Helsinki

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Aberrations in the regulatory genome play a pivotal role in population-level disease predisposition. Annotation of the regulatory regions using appropriate primary tissues - instead of cell lines affected by selection and other confounding factors - could shed new light into mechanisms underlying common conditions. We test this approach in uterine leiomyomas, highly prevalent benign neoplasms of the myometrium, by creating 15-state chromatin annotations for myometrium and uterine leiomyomas. Integration with RNA-seq, ATAC-seq, HiChIP and methylation data enables us to compare the epigenomes of myometrium and ULs with distinct driver mutations, highlighting the role of bivalent regions in the neoplastic process. Subsequently, a genome wide association study meta-analysis is performed, using three different cohorts. Disease association loci are enriched at active chromatin, especially at enhancers, and harbor tumor- and driver mutation-specific chromatin states. At SATB2 locus we show the effect of the risk genotype already in the normal tissue. Integration of genome-wide association studies and deep regulatory genomics data from the correct tissue type represents a powerful approach in understanding population-level disease predisposition.

Date: 2025
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DOI: 10.1038/s41467-025-59646-w

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