HMGA2 overexpression drives a leiomyoma-like phenotype by modulating the epigenomic environment in primary myometrial cells [ATAC-seq]
With the utilization of advanced tools for genome-wide studies, the role of the epigenome in regulating gene expression is becoming more evident in both normal tissue development and disease states. Uterine fibroids, also known as leiomyomas, are a major reproductive disease that manifests as benign tumors and altered extracellular matrix composition leading to severe pathological symptoms. Several genomic alterations have been associated with leiomyoma. HMGA2 overexpression has been noted in approximately 10% of all patients with leiomyoma. HMGA2 is a chromatin-targeted protein and is therefore an important contributor to altered transcriptomic outcomes. However, due to a lack of specific antibodies against HMGA2 and appropriate in vitro cellular models, there is a lack in understanding of HMGA2 interaction with and regulation of chromatin in the context of leiomyoma. To address this gap, we engineered primary myometrial cells that express V5-tagged HMGA2 at levels comparable to those observed in leiomyoma. We observed transcriptomic and H3K27 acetylation changes that appeared to drive a leiomyoma-like phenotype in the engineered HMGA2v5 cells. HMGA2 was found to be diffusedly bound to chromatin, with most of the binding occurring at promoter- distal regions. Moreover, altered chromatin accessibility was observed in HMGA2v5 cells, with enrichment of AP-1 family transcription factor binding motifs at various sites. Thus, our study suggests that overexpression of HMGA2 modulates the genomic architecture of myometrial cells to cause leiomyoma-like gene expression and epigenomic changes. Overall design: Primary myometrial cells were obtained from three patients and treated with empty or V5-tagged HMGA2 vector using lentiviral transduction. ATAC libraries were generated from these samples and used for next generation sequencing.