{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n L3MBTL2 is a multifunctional member of the malignant brain tumor (MBT)‐domain protein family that contributes to chromatin regulation by coordinating transcriptional repression, chromatin compaction, and genome integrity. Structural studies reveal that L3MBTL2 preferentially recognizes lower methylation states on histone tails via its fourth MBT repeat and adopts a unique asymmetric architecture that underlies its broad, yet low sequence specificity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Functionally, L3MBTL2 acts as an integral component of noncanonical Polycomb repressive complexes. In embryonic stem cells, its first and second MBT repeats mediate recruitment of complexes such as PRC1‐like 4 and PRC1.6 to target promoters, thereby promoting chromatin compaction and gene silencing independent of canonical histone modification marks."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Moreover, its selective interaction with histone deacetylase 3 (HDAC3) facilitates deacetylation processes that underpin methylation‐dependent transcriptional repression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond transcriptional regulation, L3MBTL2 plays a critical role in the DNA damage response. Following the induction of DNA double-strand breaks, L3MBTL2 is ubiquitylated by RNF8 and, in turn, facilitates the recruitment of RNF168 to damaged chromatin, thereby promoting efficient repair."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In addition, genetic studies have implicated variants in L3MBTL2 in neuropsychiatric traits, suggesting that its modulation may contribute to psychiatric risk."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of gametogenesis, L3MBTL2 is highly expressed in pachytene spermatocytes and interacts with RNF8 to regulate histone ubiquitination. This function is essential for proper chromatin remodeling during meiosis and spermiogenesis, as its deficiency leads to increased DNA damage, defective synapsis, and impaired crossing-over."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Finally, recurrent gene fusion events involving L3MBTL2, such as BCOR–L3MBTL2 fusions identified in endometrial stromal sarcomas, further emphasize its potential role in tumor biology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Together, these findings position L3MBTL2 as a central regulator of chromatin structure whose activities integrate transcriptional repression, histone modification dynamics, and the DNA damage response—functions that are critical for maintaining cell identity, genomic stability, and proper developmental progression.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yahong Guo, Nataliya Nady, Chao Qi, et al. 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