Epigenetic regulation of vertebrate limb development: from field specification to tissue morphogenesis

Vertebrate limb development provides an excellent model for understanding how epigenetic mechanisms coordinate the integration of positional information and temporal signals to generate complex three-dimensional structures. An increasing body of evidence shows that chromatin-based mechanisms, including DNA methylation, histone modifications, and higher-order chromatin organization, define the competence of progenitor cells to respond to morphogenetic signals with spatial and temporal precision during limb development. This review explores how epigenetic mechanisms orchestrate and regulate the major phases of limb formation: from field specification and bud induction to morphogenesis, lineage differentiation, and programmed cell death. Here, we examine how chromatin remodeling, histone and DNA modifications, and enhancer - promoter interactions functionally converge with developmental signaling pathways to control gene expression programs that govern timing, positional identity, and cell fate decisions. Furthermore, this review highlights recent advances that link epigenetic landscapes with morphogenetic outcomes and discusses how comparative epigenomic approaches are reshaping our understanding of evolutionary diversification in limb morphology.