transcription occurred without genome-wide accumulation of the histone modifications targeted for demethylation by LSD1 at sites of LSD1 binding, and that a demethylase-defective mutant rescued LSD1 knockdown AML cells as efficiently as wild-type protein. Rather, LSD1 inhibitors disrupt the interaction of
LSD1 and RCOR1 with the SNAG-domain transcription repressor GFI1 which is bound to a discrete set of enhancers located close to transcription factor genes which regulate myeloid differentiation. Physical separation of LSD1/RCOR1 from GFI1 is required for drug-induced differentiation. The consequent inactivation of GFI1 leads to increased enhancer histone acetylation within hours which directly correlates with up regulation of nearby, subordinate genes.
- acute myeloid leukemia
Research Beacons, Institutes and Platforms
- Manchester Cancer Research Centre