HNF4α as a Master Regulator of Epigenetic Dynamics in Epithelial Cells

Hepatocyte nuclear factor 4 α (HNF4α) is a master transcriptional regulator essential for the maintenance of epithelial cell identity and function. Beyond its well-established role in controlling metabolic and differentiation programs, recent evidence highlights HNF4α as a key determinant of epithelial epigenetic reprogramming. Through direct interaction with chromatin modifiers and pioneer factors, HNF4α contributes to the establishment, maintenance, and dynamically reshaping of epithelial-specific transcriptional programs at epigenetic level. In this review, we summarize current knowledge on how HNF4α shapes chromatin organization by recruiting chromatin modifiers, modulating nucleosome positioning and regulating chromatin loop formation, thus directing tissue-specific gene expression. We also examine its direct regulation of epigenetic modifiers, as well as of epi-miRNAs and epi-lncRNAs, underscoring its role in coordinating chromatin remodeling with transcriptional networks. Finally, we address how dynamic HNF4α occupancy and activity influence context-dependent transcriptional outputs, and how disease-related alterations of its expression and function can contribute to epithelial dysfunction. Understanding the epigenetic functions of HNF4α provides new insights into epithelial biology and reveals potential therapeutic opportunities for restoring epithelial homeostasis in disease contexts.