{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Histone H3.3, encoded by nearly identical genes such as H3F3A and H3F3B, is a replication‐independent variant central to chromatin dynamics and genome regulation. In normal development and differentiated cells, H3.3 is deposited at actively transcribed regions as well as at heterochromatic domains (including telomeres and pericentromeric regions), thereby supporting proper chromatin architecture, facilitating the recruitment of chromatin modifiers such as polycomb repressive complexes, and maintaining genome stability."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In several pediatric and young adult tumors—including various high‐grade gliomas and diffuse intrinsic pontine gliomas—recurrent mutations in H3.3 (notably K27M and G34 substitutions) have emerged as key drivers of oncogenesis. These mutations disrupt normal post‐translational modifications such as H3K27 trimethylation and H3K36 methylation, thereby reprogramming gene expression, altering the epigenetic landscape, and establishing distinct molecular and anatomical tumor subgroups."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, tumor type–specific mutations—for example, the lysine‐to‐methionine substitution at residue 36 predominantly encoded by H3F3B in chondroblastoma—highlight the nuanced, context‐dependent functions of H3.3 variants in determining cellular identity and driving oncogenic programs."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Together, these findings demonstrate that H3.3 is not only critical for the regulation of transcription and maintenance of chromatin structure during normal development but that its mutation in diverse cellular contexts is sufficient to rewire epigenetic states, leading to aberrant gene expression and tumorigenesis.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Laura A Banaszynski, Duancheng Wen, Scott Dewell, et al. 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