TY - JOUR
T1 - Altered chromatin landscape and enhancer engagement underlie transcriptional dysregulation in MED12 mutant uterine leiomyomas
AU - Moyo, Mthabisi B.
AU - Parker, J. Brandon
AU - Chakravarti, Debabrata
N1 - Funding Information:
Stacy A. Kujawa and Saurabh S. Malpani obtained consent from patients and collected tissue samples for this study. Yasuhiro Omura and Amanda L. Allred performed high-throughput sequencing of all RNA-seq, ChIP-seq, and CHi-C libraries. We thank Dr. Joseph T. Bass, Dr. Grant D. Barish, and the Feinberg School of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine for providing access to the Illumina NextSeq 500 sequencing platform for this study. We would also like to thank Dr. Steven Wingett and Dr. Mikhail Spivakov for helpful discussions regarding HiCUP and CHiCAGO analysis packages, respectively. This work was supported by the Northwestern University NUSeq Core Facility and NIH grants R21HD082781, R01HD089552, and P01HD057877.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-020-14701-6
DO - 10.1038/s41467-020-14701-6
M3 - Article
C2 - 32094355
AN - SCOPUS:85079803466
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1019
ER -