DOT1L provides transcriptional memory through PRC1.1 antagonism

Area of Science:

• * Molecular biology
• * Cancer research
• * Epigenetics

Background:

• * DOT1L and Menin are crucial for MLL fusion protein (MLL-FP) oncogenic activity in leukemia.
• * The precise mechanisms of DOT1L and Menin inhibitor efficacy are not fully understood.

Purpose of the Study:

• * To elucidate the role of non-canonical Polycomb repressive complex 1.1 (PRC1.1) in cellular responses to DOT1L and Menin inhibitors.
• * To investigate the regulatory crosstalk between DOT1L, Menin, and PRC1.1 in MLL-FP-driven leukemia.

Main Methods:

• * Investigated the impact of Menin and DOT1L inhibition on histone modifications (H2AK119ub, H3K79 methylation) and PRC1.1 activity.
• * Analyzed MLL-FP target gene expression and PRC1.1 activity in response to inhibitor treatments.
• * Examined the biochemical relationship between H3K79 methylation and PRC1 activity.

Main Results:

• * Menin inhibition triggers PRC1.1-dependent H2AK119ub deposition, silencing specific MLL-FP targets.
• * DOT1L inhibition leads to a global increase in H2AK119ub due to enhanced PRC1.1 activity.
• * Enhanced PRC1.1 activity results from DOT1L-mediated H3K79 methylation loss, independent of MLL-FP displacement.
• * A direct biochemical antagonism exists between H3K79 methylation and PRC1 activity.

Conclusions:

• * PRC1.1 plays a critical role in mediating cellular responses to DOT1L and Menin inhibitors in leukemia.
• * DOT1L functions as a component of transcriptional memory exploited in leukemia.
• * This study identifies DOT1L as a key regulator balancing the MLL-Polycomb axis in leukemia.