H19 and IGF2 imprinting from embryogenesis to oncogenesis

The imprinted H19/IGF2 locus is critical for fetal development and, when dysregulated, contributes to tumorigenesis. This review examines the mechanisms regulating imprinting through DNA methyltransferases, alongside shared signaling pathways, such as PI3K/AKT, that operate across both embryonic development and tumorigenesis. Parent-of-origin methylation at this locus coordinates differential gene activity: IGF2 promotes organogenesis and placental angiogenesis through mitogenic signaling, while H19, a long non-coding RNA that serves as a precursor for miR-675-5p, prevents fetal overgrowth, regulates trophoblast invasion, and modulates epithelial-to-mesenchymal transitions (EMT). Loss of imprinting (LOI) at this locus disrupts normal gene expression, contributing to the development of cancer and imprinting disorders. Overexpression of H19 activates the PI3K/AKT pathway and silences tumor suppressor genes such as let-7b through sponging target genes and subsequently inducing EMT. While LOI of IGF2 leads to cancer through upregulation of the Wnt3 pathway. ​​H19 and IGF2 play opposing yet coordinated roles in embryogenesis, with IGF2 promoting proliferation and H19 restricting overgrowth, a balance essential for proper tissue development. When epigenetically disrupted, it enables tumors to reactivate developmental pathways that drive unchecked growth, EMT, metastasis, and resistance to apoptosis. Controlling the balance of imprinting of the H19/IGF2 locus presents a promising mechanism for future therapies.