2026-07-10 ロックフェラー大学
＜関連情報＞
- https://www.rockefeller.edu/news/40056-leukemia-cancer-epigenetics-p53/
- https://www.cell.com/molecular-cell/fulltext/S1097-2765(26)00312-6
H3K4メチル化およびp53依存性転写活性化におけるMLL4複合体の分子メカニズム Molecular mechanisms of the MLL4 complex in H3K4 methylation and p53-dependent transcription activation
Jianfeng Sun ∙ Zhiying Zhang ∙ You Yu ∙ … ∙ Linas Urnavicius ∙ Dinshaw J. Patel ∙ Robert G. Roeder
Molecular Cell Published:May 29, 2026
DOI:https://doi.org/10.1016/j.molcel.2026.05.006
Highlights
- MLL4 complex function is regulated by three structurally rigid modules
- ASH2L-acetylated H3 contacts mediate nucleosome recognition by MLL4C
- Elucidation of a complete model of the nine-subunit MLL4 fusion complex
- MLL4C-p53 interactions mediate p53-dependent transcription activation
Summary
Mammalian H3K4 mono-methyltransferase MLL4 plays a critical role in enhancer-mediated gene activation. Here, we utilized a reconstituted MLL4 “fusion” complex (MLL4FC) for structural and functional analyses and revealed that MLL4 function is regulated by three structurally rigid modules, namely, SET-ASH2L-DPY30, RBBP5-WDR5, and PHD-FYR. Notably, the PHD-FYR module is evolutionarily conserved across MLL1-4 and is essential for MLL4- and p53-dependent transcription. Combining results from cryo-EM and crosslinking mass spectrometry, we obtained a complete model of MLL4FC and elucidated its functional interactions with p53. Genomic analyses in HCT116 cells further showed that MLL4 colocalizes with p53 at p53 target genes and that MLL4 knockout results in a marked reduction in the expression of p53-regulated genes, accompanied by reduced p53 chromatin occupancy. These findings provide molecular insights into the catalytic and non-catalytic transcriptional functions of the MLL4 complex in establishing active enhancers and facilitating p53-dependent transcription activation.
