MLL4 binds TET3

Dustin C Becht; Sk Abdul Mohid; Ji-Eun Lee; Mohamad Zandian; Caroline Benz; Soumi Biswas; Vikrant Kumar Sinha; Ylva Ivarsson; Kai Ge; Yi Zhang; Tatiana G Kutateladze

doi:10.1016/j.str.2024.03.005

MLL4 binds TET3

Structure. 2024 Mar 27:S0969-2126(24)00087-X. doi: 10.1016/j.str.2024.03.005. Online ahead of print.

Authors

Affiliations

¹ Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
² Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
³ Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
⁴ Department of Chemistry - BMC, Uppsala University, 751 23 Uppsala, Sweden.
⁵ Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address: yi.zhang26@case.edu.
⁶ Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address: tatiana.kutateladze@cuanschutz.edu.

PMID: 38579707
DOI: 10.1016/j.str.2024.03.005

Abstract

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 (MLL4_PHD6) 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-MLL4_PHD6 complex and binding assays show that, like histone H4 tail, TET3 occupies the hydrophobic site of MLL4_PHD6, and that this interaction is conserved in the seventh PHD finger of homologous MLL3 (MLL3_PHD7). 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.

Keywords: MLL4; PHD finger; TET3; interaction; structure.