Human IGF2 Gene Epigenetic and Transcriptional Regulation: At the Core of Developmental Growth and Tumorigenic Behavior

Regulation of the human IGF2 gene displays multiple layers of control, which secures a genetically and epigenetically predetermined gene expression pattern throughout embryonal growth and postnatal life. These predominantly nuclear regulatory mechanisms converge on the function of the IGF2-H19 gene cluster on Chromosome 11 and ultimately affect IGF2 gene expression. Deregulation of such control checkpoints leads to the enhancement of IGF2 gene transcription and/or transcript stabilization, ultimately leading to IGF-II peptide overproduction. This type of anomaly is responsible for the effects observed in terms of both abnormal fetal growth and increased cell proliferation, typically observed in pediatric overgrowth syndromes and cancer. We performed a review of relevant experimental work on the mechanisms affecting the human IGF2 gene at the epigenetic, transcriptional and transcript regulatory levels. The result of our work, indeed, provides a wider and diversified scenario for IGF2 gene activation than previously envisioned by shedding new light on its extended regulation. Overall, we focused on the functional integration between the epigenetic and genetic machinery driving its overexpression in overgrowth syndromes and malignancy, independently of the underlying presence of loss of imprinting (LOI). The molecular landscape provided at last strengthens the role of IGF2 in cancer initiation, progression and malignant phenotype maintenance. Finally, this review suggests potential actionable targets for IGF2 gene- and regulatory protein target-degradation therapies.

Automated summary

The regulation of the human IGF2 gene is controlled by multiple mechanisms at the genetic and epigenetic levels, ultimately affecting gene expression. Deregulation of these mechanisms can lead to overexpression of IGF2, resulting in abnormal fetal growth and increased cell proliferation observed in overgrowth syndromes and cancer. Our review sheds new light on the extended regulation of IGF2 gene activation, emphasizing the integration between epigenetic and genetic machinery. It also suggests potential targets for therapeutic strategies aimed at degrading the IGF2 gene and regulatory proteins.