Menin "reads" H3K79me2 mark in a nucleosomal context

Area of Science:

• Epigenetics
• Molecular Biology
• Structural Biology

Background:

• Histone methylation, specifically H3K79 methylation, plays a crucial role in gene regulation.
• The downstream effects of H3K79 methylation are not fully understood due to limited knowledge of its interacting proteins (readers).

Purpose of the Study:

• To identify proteins that recognize H3K79 dimethylation (H3K79me2) in a nucleosomal context.
• To elucidate the structural basis of menin's interaction with H3K79me2 nucleosomes.

Main Methods:

• Development of a nucleosome-based photoaffinity probe to capture H3K79me2-binding proteins.
• Quantitative proteomics to identify proteins interacting with the probe.
• Cryo-electron microscopy to determine the structure of menin bound to an H3K79me2 nucleosome.

Main Results:

• Menin was identified as a specific reader of H3K79me2.
• The cryo-EM structure revealed menin's interaction with the H3K79me2 nucleosome via its fingers and palm domains.
• Menin recognizes the H3K79me2 mark through a π-cation interaction.
• Menin selectively associates with H3K79me2-modified chromatin in gene bodies within cells.

Conclusions:

• Menin acts as a direct reader of the H3K79me2 epigenetic mark.
• The structural insights provide a molecular basis for how menin recognizes H3K79me2 on nucleosomes.
• This finding advances the understanding of epigenetic regulation and the role of menin in chromatin biology.