Interplay between pioneer transcription factors and epigenetic modifiers in cell reprogramming

The generation of induced pluripotent stem cells (iPSCs) from differentiated somatic cells by Yamanaka factors, including pioneer transcription factors (TFs), has greatly reshaped our traditional understanding of cell plasticity and demonstrated the remarkable potential of pioneer TFs. In addition to iPSC reprogramming, pioneer TFs are pivotal in direct reprogramming or transdifferentiation where somatic cells are converted into different cell types without passing through a pluripotent state. Pioneer TFs initiate a reprogramming process through chromatin opening, thereby establishing competence for new gene regulatory programs. The action of pioneer TFs is both influenced by and exerts influence on epigenetic regulation. Despite significant advances, many direct reprogramming processes remain inefficient, which limits their reliability for clinical applications. In this review, we discuss the molecular mechanisms underlying pioneer TF-driven reprogramming, with a focus on their interactions with epigenetic modifiers, including Polycomb repressive complexes (PRCs), nucleosome remodeling and deacetylase (NuRD) complexes, and the DNA methylation machinery. A deeper understanding of the dynamic interplay between pioneer TFs and epigenetic modifiers will be essential for advancing reprogramming technologies and unlocking their full clinical potential.