A Unique Promoter Architecture Defines Menin-KMT2A Complex Selectivity

A composite promoter architecture—CpG islands flanked by several-kilobase A/T-rich AT-flanks—marks high Menin-KMT2A occupancy at developmental and leukemia-associated genes.

• Why it matters: Selective binding of chromatin-regulatory complexes is key for gene regulation, but the DNA sequence features that determine Menin-KMT2A targeting and drug sensitivity are unclear.
• What they did: Using interpretable machine learning, the study defined the CpG island–AT-flank architecture, then used genetic deletion and chromatin-contact analyses to test how AT-flanks affect KMT2A retention; LEDGF was identified as an A/T-rich DNA-associated factor required for Menin engagement.
• The result: AT-flank extent is linked to differential KMT2A loss after pharmacologic disruption of the Menin-KMT2A interaction, and the same architecture also distinguishes promoters with high canonical PRC1 occupancy across diverse cell types.

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