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Chromatin state origins of uterine leiomyoma
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Journal Article
Chromatin state origins of uterine leiomyoma
2025
Overview
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.
The chromatin state origins of uterine leiomyoma (UL) remain to be explored. Here, the authors integrate data from genome-wide association studies and deep regulatory genomics data from myometrium and the three UL subclasses to understand population-level disease predisposition at chromatin state level.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 49/1
/ 49/15
/ 49/23
/ Female
/ Fibroids
/ Gene Expression Regulation, Neoplastic
/ Genetic Predisposition to Disease
/ Genome-wide association studies
/ Genome-Wide Association Study
/ Genomes
/ Genomics
/ Humanities and Social Sciences
/ Humans
/ Loci
/ Matrix Attachment Region Binding Proteins - genetics
/ Mutation
/ Origins
/ Science
/ Uterine Neoplasms - genetics
/ Uterine Neoplasms - metabolism
/ Uterine Neoplasms - pathology
/ Uterus
