MLL4 binds TET3

• Published in: Structure (London) Vol. 32; no. 6; pp. 706 - 714.e3
• Main Authors: Becht, Dustin C., Mohid, Sk Abdul, Lee, Ji-Eun, Zandian, Mohamad, Benz, Caroline, Biswas, Soumi, Sinha, Vikrant Kumar, Ivarsson, Ylva, Ge, Kai, Zhang, Yi, Kutateladze, Tatiana G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.06.2024
• Subjects: Animals; Binding Sites; Dioxygenases - chemistry; Dioxygenases - genetics; Dioxygenases - metabolism; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Histone-Lysine N-Methyltransferase - chemistry; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Humans; interaction; Mice; MLL4; Models, Molecular; Myeloid-Lymphoid Leukemia Protein - chemistry; Myeloid-Lymphoid Leukemia Protein - genetics; Myeloid-Lymphoid Leukemia Protein - metabolism; PHD finger; Protein Binding; Proto-Oncogene Proteins - chemistry; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; structure; TET3; interaction; MLL4; PHD finger; structure; TET3
• ISSN: 0969-2126; 1878-4186; 1878-4186
• DOI: 10.1016/j.str.2024.03.005

Human mixed lineage leukemia 4 (MLL4), also known as KMT2D, regulates cell type specific transcriptional programs through enhancer activation. Along with the catalytic methyltransferase domain, MLL4 contains seven less characterized plant homeodomain (PHD) fingers. Here, we report that the sixth PHD finger of MLL4 (MLL4PHD6) binds to the hydrophobic motif of ten-eleven translocation 3 (TET3), a dioxygenase that converts methylated cytosine into oxidized derivatives. The solution NMR structure of the TET3-MLL4PHD6 complex and binding assays show that, like histone H4 tail, TET3 occupies the hydrophobic site of MLL4PHD6, and that this interaction is conserved in the seventh PHD finger of homologous MLL3 (MLL3PHD7). Analysis of genomic localization of endogenous MLL4 and ectopically expressed TET3 in mouse embryonic stem cells reveals a high degree overlap on active enhancers and suggests a potential functional relationship of MLL4 and TET3. [Display omitted] •PHD6 finger of MLL4 (MLL4PHD6) binds to ten-eleven translocation 3 (TET3)•TET3 and histone H4K16ac tail occupy the same hydrophobic site of MLL4PHD6•Binding to TET3 is conserved in the PHD finger of homologous MLL3 (MLL3PHD7)•TET3 and MLL4 binding sites overlap on active enhancers in mouse ESCs The human methyltransferase MLL4 and the dioxygenase TET3 mediate fundamental DNA-templated nuclear processes. Becht et al. report the structural mechanism by which MLL4 binds to TET3.