Abstract

Histones are critical for eukaryotic cell survival, supporting and packaging DNA into chromatin domains that define gene expression and cellular identity. Fundamental to the establishment of these domains is the adequate histone supply that is tightly regulated from the moment histones are transcribed, synthesized, and recycled, to when they are degraded. In this review, we describe and emphasize each step of the histone supply chain and its impact on chromatin structure and cellular identity. Given the robust studies on histones H3 and H4 supply, we primarily discuss these nucleosome components and their variants while briefly touching on H2A and H2B dynamics. We also highlight central proteins that supervise these processes and relay key studies that explore the consequences and clinical impact of limiting or altering the histone supply chain. Together, these insights underscore the importance of histone homeostasis as a critical determinant of genome stability and cell fate. © 2025 The Author(s).