Beyond the linker: Histone H1 as a dynamic epigenetic hub governing chromatin plasticity and disease pathogenesis.

Chromatin, a higher-order structure of eukaryotic genomes, is dynamically regulated and plays pivotal roles in gene regulation and cellular homeostasis. Nucleosomes are the basic functional units of chromatin. Each nucleosome consists of a histone octamer (H2A, H2B, H3, and H4) wrapped by DNA. While linker histone H1 (H1) facilitates and stabilizes DNA binding to histones, it also critically governs higher-order chromatin organization and transcriptional regulation. Although post-translational modifications (PTMs) of core histones have been extensively characterized, the functional significance of H1 has historically been underappreciated. Emerging research reveals that H1 is not merely a structural component but a dynamic epigenetic regulator governing chromatin higher-order organization, transcriptional programs, and cellular differentiation. H1 undergoes diverse post-translational modifications, including acetylation, methylation, phosphorylation, and ubiquitination, which fine-tune its interactions with chromatin and non-chromatin partners. Dysregulation of H1 expression, localization, or PTMs is implicated in cancer, neurodegenerative disorders, metabolic diseases, and immune dysfunctions. This review synthesizes recent advances in H1 biology, highlighting its isoform-specific functions, PTM-mediated regulatory networks, and translational potential as a diagnostic marker and therapeutic target.