Abstract
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.
Highlights
Uterine leiomyomas 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
Principal component analysis of the most variable genes revealed that 43% of the variance (PC1) is explained by the disease state, with biological replicates co-segregating based on tissue type (Fig. 1b). This suggests that the changes in gene expression between normal and mediator of transcription subunit 12 (MED12) mutant disease tissue types are primarily attributable to biological pathways that are important for the development and maintenance of the leiomyoma disease state
Using modified methods adapted for use with fresh tissue samples, we provide an extensive transcriptomic and epigenomic characterization of normal myometrium and MED12 mutant leiomyoma tissues, thereby yielding a near-faithful snapshot of the differences between myometrium and leiomyoma tissues under native conditions
Summary
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. 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. Leiomyomas are clonal tumors that originate from the smooth muscle layer of the uterine wall, the myometrium[2] They are primarily characterized by an increased deposition of a disorganized extracellular matrix (ECM), resulting in benign neoplasms of varying size[3,4]. The existence of dynamic or altered contacts in human disease as a result of epigenetic changes to chromatin has not been investigated
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