MLL4 binds TET3.

Area of Science:

• Epigenetics and transcriptional regulation
• Protein-protein interactions in gene expression
• Biochemistry and structural biology

Background:

• Mixed lineage leukemia 4 (MLL4), also known as KMT2D, is crucial for enhancer activation and cell-type specific transcription.
• MLL4 possesses a catalytic domain and seven plant homeodomain (PHD) fingers, with limited characterization of the latter.
• Ten-eleven translocation 3 (TET3) is a dioxygenase involved in DNA demethylation, converting methylated cytosine to oxidized forms.

Purpose of the Study:

• To investigate the interaction between MLL4 and TET3.
• To elucidate the structural basis of the MLL4-TET3 binding.
• To explore the functional implications of this interaction in gene regulation.

Main Methods:

• Solution Nuclear Magnetic Resonance (NMR) structure determination of the TET3-MLL4 PHD6 complex.
• Biochemical binding assays to characterize the interaction.
• Genomic localization analysis of MLL4 and TET3 in mouse embryonic stem cells.

Main Results:

• The sixth PHD finger of MLL4 (MLL4 PHD6) directly binds to a hydrophobic motif on TET3.
• Structural analysis reveals TET3 occupies a hydrophobic site on MLL4 PHD6, similar to histone H4.
• This interaction is conserved in the seventh PHD finger of MLL3 (MLL3 PHD7).
• Endogenous MLL4 and ectopically expressed TET3 show significant overlap in their genomic localization on active enhancers.

Conclusions:

• MLL4 PHD6 interacts with TET3 through a conserved hydrophobic binding site.
• The overlapping genomic distribution suggests a functional relationship between MLL4 and TET3 at active enhancers.
• This interaction may play a role in coordinating epigenetic modifications and DNA demethylation for transcriptional control.