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Nat Commun. 2020 Feb 24;11(1):1019. doi: 10.1038/s41467-020-14701-6.

Altered chromatin landscape and enhancer engagement underlie transcriptional dysregulation in MED12 mutant uterine leiomyomas.

Author information

1
Driskill Graduate Program in Life Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
2
Department of Obstetrics and Gynecology, Division of Reproductive Science in Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
3
Department of Obstetrics and Gynecology, Division of Reproductive Science in Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. debu@northwestern.edu.
4
Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. debu@northwestern.edu.
5
Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, 60611, USA. debu@northwestern.edu.

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.

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