Chromatin state origins of uterine leiomyoma

TL;DR

This study explores how chromatin states in uterine tissue contribute to the development of uterine leiomyomas, using regulatory genomics and genome-wide data.

Contribution

The study introduces chromatin annotations for myometrium and leiomyomas, linking disease-associated genetic variants to specific chromatin states.

Findings

Chromatin states in myometrium and leiomyomas reveal bivalent regions important in neoplastic processes.

Disease association loci are enriched at active chromatin, particularly enhancers.

Risk genotypes at the SATB2 locus affect chromatin states even in normal tissue.

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.

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.

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