Article Dans Une Revue Cellular and Molecular Life Sciences Année : 2023

Clustered PHD domains in KMT2/MLL proteins are attracted by H3K4me3 and H3 acetylation-rich active promoters and enhancers

Résumé

Histone lysine-specific methyltransferase 2 (KMT2A-D) proteins, alternatively called mixed lineage leukemia (MLL1-4) proteins, mediate positive transcriptional memory. Acting as the catalytic subunits of human COMPASS-like complexes, KMT2A-D methylate H3K4 at promoters and enhancers. KMT2A-D contain understudied highly conserved triplets and a quartet of plant homeodomains (PHDs). Here, we show that all clustered (multiple) PHDs localize to the well-defined loci of H3K4me3 and H3 acetylation-rich active promoters and enhancers. Surprisingly, we observe little difference in binding pattern between PHDs from promoter-specific KMT2A-B and enhancer-specific KMT2C-D. Fusion of the KMT2A CXXC domain to the PHDs drastically enhances their preference for promoters over enhancers. Hence, the presence of CXXC domains in KMT2A-B, but not KMT2C-D, may explain the promoter/enhancer preferences of the full-length proteins. Importantly, targets of PHDs overlap with KMT2A targets and are enriched in genes involved in the cancer pathways. We also observe that PHDs of KMT2A-D are mutated in cancer, especially within conserved folding motifs (Cys4HisCys2Cys/His). The mutations cause a domain loss-of-function. Taken together, our data suggest that PHDs of KMT2A-D guide the full-length proteins to active promoters and enhancers, and thus play a role in positive transcriptional memory.
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Dates et versions

hal-04725022 , version 1 (07-10-2024)

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Anna Maria Stroynowska-Czerwinska, Magdalena Klimczak, Michal Pastor, Asgar Abbas Kazrani, Katarzyna Misztal, et al.. Clustered PHD domains in KMT2/MLL proteins are attracted by H3K4me3 and H3 acetylation-rich active promoters and enhancers. Cellular and Molecular Life Sciences, 2023, 80 (1), pp.23. ⟨10.1007/s00018-022-04651-1⟩. ⟨hal-04725022⟩
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