Engineered uterine primary myometrial cells with HMGA2 overexpression display a leiomyoma-like transcriptional and epigenomic phenotype

Abstract

To determine if engineered HMGA2 overexpressing uterine primary myometrial cells recapitulate the transcriptional and epigenomic features of HMGA2-subtype leiomyomas. Isolated primary, "normal" myometrial cells from 3 patients were engineered to overexpress HMGA2 to determine how HMGA2 establishes transcriptomic and epigenomic features of HMGA2-overexpressing leiomyoma. Academic research laboratory PATIENTS: Primary myometrial cells were isolated from normal myometrium obtained from three patients undergoing hysterectomy. Not applicable MAIN OUTCOME MEASURES: Determined genome-wide transcriptomic and epigenomic features of engineered HMGA2-overexpressing uterine primary myometrial cells. Engineered HMGA2-V5-overexpressing primary myometrial cells approximated the HMGA2 expression level observed in HMGA2-overexpression subtype leiomyoma. HMGA2-V5 expression resulted in differential expression of 1612 genes (FDR < 0.05) which were found to be enriched in pathways associated with leiomyoma formation, including extracellular matrix organization. Comparative gene expression analysis between HMGA2-V5 engineered primary cells and HMGA2-overexpression subtype leiomyoma revealed significant overlap of differentially expressed genes. Mechanistically, HMGA2-V5 overexpression resulted in 41,323 regions with differential H3K27ac deposition (FDR < 0.05) and 205,605 regions of altered chromatin accessibility (FDR < 0.05). Transcription factor binding site analysis implicated the AP-1 family of transcription factors. • What clinical problem is addressed by these studies? About 10-15% of the uterine leiomyoma cases exhibit increased expression of HMGA2; our study addresses the primary role of HMGA2 overexpression in the pathogenesis of leiomyoma. • What are the key findings? Ectopic expression of HMGA2 in primary myometrial cells transforms transcriptional and epigenomic machinery in these cells which to some extent resemble features of leiomyoma. • How do these findings apply to human fertility or the reproductive process? Our study provides a comprehensive analysis into the changes occurring in epigenome of myometrial cells when HMGA2 is overexpressed. Because epigenome can be targeted with drugs, therefore understanding alterations in epigenome provides new avenues for treating leiomyoma which affects reproductive age women.