Integrative Network Meta-Analysis Reveals Estrogen-Mediated RUNX2PDLIM3microRNA Crosstalk via ERG Signaling: Implications for Bone and Tissue Regeneration

Abstract

Estrogens govern the female reproductive cycle indefinitely. Estrogens, including estrone (E1), estradiol (E2), estriol (E3), and estetrol (E4), regulate the female life cycle since early embryonic stages and play a crucial role in development, metabolism, and cell function. Throughout evolution, estrogen has regulated reproduction by affecting reproductive organ development and behavior. Estrogen impacts all vertebrates, including fish, and has a role in physiological and pathological states in both genders. The RUNX-2 gene is a member of the RUNX family of transcription factors and encodes a nuclear protein with a Runt DNA-binding domain. This protein is essential for osteoblastic differentiation and skeletal morphogenesis and acts as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. The protein can bind DNA both as a monomer or, with more affinity, as a subunit of a heterodimeric complex. In 2022, a study was conducted to characterize novel genes that are regulated by estrogen binding to its receptors ( or {beta}). The PDLIM3 gene, with a coefficient of variation (CV) of 0.083, received the most stable CV score among other genes. Our integrative research uncovers a unique regulatory cascade in which estrogen binding to ER/{beta} enhances PDLIM3 expression, then modulating the expression of miR-9, miR-10, and the newly identified miR-6769b, finally activating RUNX2 transcription.