{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Histone H4 “codes” – that is, the post‐translational modifications localized on the H4 tail – play central roles in orchestrating chromatin dynamics. For example, acetylation of lysine 16 on H4 (H4‐K16Ac) relaxes chromatin by preventing the formation of compact fibers and by altering nucleosome–nucleosome interactions, thereby modulating both higher order structure and access of remodeling enzymes to DNA (for example."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, specific methylation events on H4 – such as dimethylation of lysine 20 – serve as binding platforms for key effectors; the recognition of H4‐K20me2 by tandem tudor domains, for instance, underlies the recruitment of important DNA repair proteins that direct double‐strand break repair and genome stability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, enzymes that “write” and “erase” these modifications – including histone acetyltransferases such as Tip60 and deacetylases from the sirtuin family – modulate not only chromatin accessibility but also functional interactions with nonhistone proteins. Through dynamic cycles of acetylation and deacetylation (for example, by SIRT1 and SIRT2), histone H4 modifications contribute to processes as diverse as cell cycle progression, centromere assembly, DNA damage response and even metabolic regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, alteration in the “H4 code” is implicated in pathologic states including oncogenesis, aging, and aberrant transcription. Changes in H4 acetylation and methylation can influence the recruitment of chromatin regulators and transcription factors – as seen when bromodomain proteins interact with diacetylated H4 motifs or when altered recognition by repair factors shifts the balance between homologous recombination and nonhomologous end joining."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Such multifaceted regulatory mechanisms highlight how the combinatorial readout of H4 modifications directs essential cellular outcomes by controlling chromatin structure and gene expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, the “H4 code” functions as a versatile epigenetic platform. Its modifications are key determinants of chromatin compaction, serve as docking sites for effector proteins in DNA repair and transcription, and are dynamically modulated to integrate signals from metabolism, cell cycle status and extracellular cues. Collectively, these studies support a model in which histone H4 modifications function as critical regulators of chromatin plasticity and genome integrity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}, {"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "3"}, {"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Michael Shogren-Knaak, Haruhiko Ishii, Jian-Min Sun, et al. 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