{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Histone H4 plays a central role in regulating chromatin structure and function through a variety of post‐translational modifications that modulate genomic accessibility, transcription, DNA repair, and higher order chromatin organization. For example, acetylation of histone H4 at lysine 16 (H4‐K16Ac) has been shown to inhibit the formation of compact chromatin fibers and to impede nucleosome remodeling, thereby facilitating a more open chromatin conformation that can influence both remodeling enzyme activity and protein–chromatin interactions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In parallel, removal of this acetyl mark by sirtuin deacetylases such as SIRT2 is critical during the cell cycle to promote chromatin condensation at mitosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Acetylated H4 tails also serve as specific binding platforms for bromodomain‐containing proteins; for instance, Brd4 recognizes di‐ and tetraacetylated H4, thereby linking histone acetylation status to transcriptional regulation and chromatin targeting."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to acetylation, methylation of H4 residues—most notably at lysine 20—plays a key role in orchestrating DNA damage responses. Dimethylation of H4 at lysine 20 (H4K20me2) is selectively recognized by DNA repair factors such as 53BP1, which is essential for proper double‐strand break repair."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Moreover, the dynamic regulation of H4 methylation includes enzymatic demethylation (for example, removal of H4K20me1 by PHF8), which impacts chromatin structure and cell cycle progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Structural studies further underscore the functional importance of H4 in nucleosome composition; incorporation into CENP-A–H4 heterotetramers confers a unique rigidity that is critical for centromere identity and genome stability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Together, these findings illustrate that histone H4 modifications—from acetylation to methylation—act in concert to regulate chromatin dynamics, thereby modulating key cellular processes such as transcription, DNA repair, and cell cycle progression.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Michael Shogren-Knaak, Haruhiko Ishii, Jian-Min Sun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Histone H4-K16 acetylation controls chromatin structure and protein interactions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1124000"}], "href": "https://doi.org/10.1126/science.1124000"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16469925"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16469925"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Alejandro Vaquero, Michael B Scher, Dong Hoon Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.1412706"}], "href": "https://doi.org/10.1101/gad.1412706"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16648462"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16648462"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Anup Dey, Farideh Chitsaz, Asim Abbasi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1433065100"}], "href": "https://doi.org/10.1073/pnas.1433065100"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12840145"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12840145"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Maria Victoria Botuyan, Joseph Lee, Irene M Ward, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2006.10.043"}], "href": "https://doi.org/10.1016/j.cell.2006.10.043"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17190600"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17190600"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Wen Liu, Bogdan Tanasa, Oksana V Tyurina, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PHF8 mediates histone H4 lysine 20 demethylation events involved in cell cycle progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature09272"}], "href": "https://doi.org/10.1038/nature09272"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20622854"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20622854"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Ben E Black, Daniel R Foltz, Srinivas Chakravarthy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural determinants for generating centromeric chromatin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature02766"}], "href": "https://doi.org/10.1038/nature02766"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15282608"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15282608"}]}]}]}