MORF and MOZ acetyltransferases target unmethylated CpG islands through the winged helix domain

Abstract

Human acetyltransferases MOZ and MORF are implicated in chromosomal translocations associated with aggressive leukemias. Oncogenic translocations involve the far amino terminus of MOZ/MORF, the function of which remains unclear. Here, we identified and characterized two structured winged helix (WH) domains, WH1 and WH2, in MORF and MOZ. WHs bind DNA in a cooperative manner, with WH1 specifically recognizing unmethylated CpG sequences. Structural and genomic analyses show that the DNA binding function of WHs targets MORF/MOZ to gene promoters, stimulating transcription and H3K23 acetylation, and WH1 recruits oncogenic fusions to HOXA genes that trigger leukemogenesis. Cryo-EM, NMR, mass spectrometry and mutagenesis studies provide mechanistic insight into the DNA-binding mechanism, which includes the association of WH1 with the CpG-containing linker DNA and binding of WH2 to the dyad of the nucleosome. The discovery of WHs in MORF and MOZ and their DNA binding functions could open an avenue in developing therapeutics to treat diseases associated with aberrant MOZ/MORF acetyltransferase activities.

Atypical histone targets of PHD fingers

“…Mutations of the H3K14acyl-binding residues in DPF of DPF2 have been associated with neurological disorders, including the Coffin-Siris syndrome ( 46 ). MOZ and MORF are catalytic subunits of the MOZ/MORF acetyltransferase complexes that acetylate H3K23 ( 43 , 47 ). These complexes regulate expression of the HOX genes and are required for development, hematopoiesis, and skeletogenesis ( 48 ).…”

“…Aberrant catalytic activities of MOZ/MORF caused by chromosomal translocations and mutations are linked to aggressive forms of leukemias and developmental diseases. Binding of MOZ/MORF DPFs to acylated H3K14 promotes acetylation of H3K23 by the native complexes and stabilizes these complexes at target gene promoters to activate transcription ( 43 , 47 ).…”

Prokaryotic winged helix domains as dsDNA adenine methylation sensors

“…The identification of prokaryotic winged helix domains as sensors of adenine methylation contrasts with the role of some eukaryotic winged helix domains as sensors of non-methylated CpG (39)(40)(41). Superposition of the winged helix domains of prokaryotic DpnI (28) and eukaryotic KAT6A (a.k.a.…”

“…However, other DNA binding modes are also possible in special cases (37,38). A recent example for such alternative binding modes is the complexes of eukaryotic winged helix domains with dsDNA containing non-methylated CpG (39)(40)(41). A winged helix motif in a restriction endonuclease (REase) was first noticed in the DNA binding domain of FokI (36), but this particular wH domain does not appear to be involved in DNA interactions.…”

Characterization of winged helix domain fusion endonucleases as N6-methyladenine-dependent type IV restriction systems

“…However, other DNA-binding modes are also possible in special cases ( Gajiwala et al, 2000 ; Wolberger and Campbell, 2000 ). A recent example of such alternative binding modes is the complexes of eukaryotic winged helix domains with dsDNA containing non-methylated CpG ( Stielow et al, 2021 ; Becht et al, 2023 ; Weber et al, 2023 ). A winged helix motif in a restriction endonuclease (REase) was first noticed in the DNA-binding domain of FokI ( Wah et al, 1997 ), but this particular wH domain does not appear to be involved in interactions with DNA.…”