Engineered uterine primary myometrial cells with high-mobility group AT-hook 2 overexpression display a leiomyoma-like transcriptional and epigenomic phenotype.

OBJECTIVE: To determine if engineered high-mobility group AT-hook 2 (HMGA2) overexpressing uterine primary myometrial cells recapitulate the transcriptional and epigenomic features of HMGA2-subtype leiomyomas. DESIGN: Isolated primary, "normal" myometrial cells from three patients were engineered to overexpress HMGA2 to determine how HMGA2 establishes transcriptomic and epigenomic features of HMGA2-overexpressing leiomyoma. SETTING: Academic research laboratory. PATIENT(S): Primary myometrial cells were isolated from normal myometrium obtained from three patients undergoing hysterectomy. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Determined genome-wide transcriptomic and epigenomic features of engineered HMGA2-overexpressing uterine primary myometrial cells. RESULT(S): Engineered HMGA2-V5-overexpressing primary myometrial cells approximated the HMGA2 expression level observed in HMGA2-overexpression subtype leiomyoma. High-mobility group AT-hook 2-V5 expression resulted in differential expression of 1,612 genes (false discovery rate [FDR] < 0.05) that 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. CONCLUSION(S): High-mobility group AT-hook 2 overexpression induces leiomyoma-like transcriptomic and epigenomic modulations in myometrial cells.