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Altered chromatin landscape and enhancer engagement underlie transcriptional dysregulation in MED12 mutant uterine leiomyomas
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Altered chromatin landscape and enhancer engagement underlie transcriptional dysregulation in MED12 mutant uterine leiomyomas
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Altered chromatin landscape and enhancer engagement underlie transcriptional dysregulation in MED12 mutant uterine leiomyomas
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Journal Article
Altered chromatin landscape and enhancer engagement underlie transcriptional dysregulation in MED12 mutant uterine leiomyomas
2020
Overview
Uterine leiomyomas (fibroids) are a major source of gynecologic morbidity in reproductive age women and are characterized by the excessive deposition of a disorganized extracellular matrix, resulting in rigid benign tumors. Although down regulation of the transcription factor AP-1 is highly prevalent in leiomyomas, the functional consequence of AP-1 loss on gene transcription in uterine fibroids remains poorly understood. Using high-resolution ChIP-sequencing, promoter capture Hi-C, and RNA-sequencing of matched normal and leiomyoma tissues, here we show that modified enhancer architecture is a major driver of transcriptional dysregulation in
MED12
mutant uterine leiomyomas. Furthermore, modifications in enhancer architecture are driven by the depletion of AP-1 occupancy on chromatin. Silencing of AP-1 subunits in primary myometrium cells leads to transcriptional dysregulation of extracellular matrix associated genes and partly recapitulates transcriptional and epigenetic changes observed in leiomyomas. These findings establish AP-1 driven aberrant enhancer regulation as an important mechanism of leiomyoma disease pathogenesis.
Somatic mutations in
MED12
have been implicated as the causal genetic lesion in the majority of uterine leiomyomas. Here, the authors profile the chromatin landscape of matched normal and leiomyoma tissues and find that changes in enhancer acetylation, enhancer-promoter interaction strength, differential enhancer usage and transcription factor AP-1 occupancy are significant drivers of transcriptional dysregulation in
MED12
mutant leiomyomas.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 45/15
/ Adult
/ Chromatin Immunoprecipitation Sequencing
/ Cyclin-Dependent Kinase 8 - metabolism
/ Enhancer Elements, Genetic - genetics
/ Female
/ Fibroids
/ Gene Expression Regulation, Neoplastic
/ Genetic Predisposition to Disease
/ Humanities and Social Sciences
/ Humans
/ Mediator Complex - metabolism
/ Mutants
/ Mutation
/ RNA
/ RNA-Seq
/ Science
/ Transcription Factor AP-1 - genetics
/ Transcription Factor AP-1 - metabolism
/ Tumors
/ Uterine Neoplasms - genetics
/ Uterine Neoplasms - pathology
/ Uterus
