EZH2 in Neurogenesis: An Epigenetic Conductor of Neural Fate

Enhancer of Zeste Homolog 2 (EZH2), the catalytic component of Polycomb Repressive Complex 2 (PRC2), is a key epigenetic regulator of neural development through its ability to catalyze histone H3 lysine 27 trimethylation (H3K27me3). Emerging evidence demonstrates that EZH2 plays essential roles in neural stem cell maintenance, lineage specification, neuronal differentiation, and gliogenesis by orchestrating dynamic chromatin states and transcriptional programs. Beyond its canonical gene-silencing function, EZH2 interacts with major developmental signaling pathways, including Notch, Wingless/Integrated signaling pathway (Wnt)/β-catenin, bone morphogenetic protein (BMP)/transforming growth factor beta (TGF-β), and Phosphoinositide 3-kinase (PI3K)/Protein kinase B (AKT), enabling the integration of environmental and developmental cues into epigenetic regulation. In this review, we synthesize current knowledge regarding the molecular mechanisms by which EZH2 regulates neurogenesis during embryonic development and in adult neurogenic niches. We further discuss emerging evidence for non-canonical EZH2 activities, its role in neurological disorders and brain tumorigenesis, and its potential as a therapeutic target in regenerative medicine. Collectively, the available evidence supports a model in which EZH2 functions as a dynamic epigenetic gatekeeper that coordinates neural cell-state transitions by balancing stem cell self-renewal and differentiation. Understanding these context-dependent functions of EZH2 will provide new insights into neural development and facilitate the development of targeted epigenetic therapies for neurological diseases and brain cancers.