A Unique Promoter Architecture Defines Menin-KMT2A Complex Selectivity

Freire, P. R.; Regalado, B.; Takeda, R.; Ener, E. T.; Wan, G.; Cutler, J. A.; Baharav, T. Z.; Brown, J.; Sharlandjieva, V.; Milne, T.; Irizarry, R. A.; Armstrong, S. A.

doi:10.64898/2026.10.30.763078

bioRxiv · 10.64898/2026.10.30.763078

A Unique Promoter Architecture Defines Menin-KMT2A Complex Selectivity

Freire, P. R.·Regalado, B.·Takeda, R.·Ener, E. T.·Wan, G.·Cutler, J. A.·Baharav, T. Z.·Brown, J.·Sharlandjieva, V.·Milne, T.·Irizarry, R. A.·Armstrong, S. A.

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Abstract

Selective occupancy of chromatin-regulatory complexes is central to developmental gene regulation, yet the sequence determinants of this selectivity remain poorly understood. Using interpretable machine learning, we identify a composite promoter architecture comprising CpG islands flanked by several-kilobase A/T-rich domains (AT-flanks) that denotes high occupancy of the Menin-KMT2A histone-modifying complex at developmental and leukemia-associated genes. Genetic deletion and chromatin-contact analyses show that AT-flanks support KMT2A retention at linked CpG islands. We identify LEDGF as an A/T-rich DNA-associated protein required for Menin engagement at AT-flanks and sustained KMT2A promoter occupancy. AT-flank extent is associated with differential KMT2A loss following pharmacologic disruption of the Menin-KMT2A interaction, providing a genomic basis for heterogeneous target sensitivity to recently approved Menin inhibitors in acute leukemia. Beyond Menin-KMT2A, the same architecture distinguishes promoters with high canonical PRC1 occupancy across diverse cell types, revealing a shared sequence organization associated with distinct chromatin-regulatory states.

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Freire, P. R., Regalado, B., Takeda, R., Ener, E. T., Wan, G., Cutler, J. A., Baharav, T. Z., Brown, J., Sharlandjieva, V., Milne, T., Irizarry, R. A., Armstrong, S. A.. 2026-11-02. A Unique Promoter Architecture Defines Menin-KMT2A Complex Selectivity. https://doi.org/10.64898/2026.10.30.763078

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