Structural and functional specificity of H3K36 methylation.

Area of Science:

• Epigenetics and Molecular Biology
• Chromatin Biology
• Genomic Stability

Background:

• Histone H3 lysine 36 methylation (H3K36me) is a critical epigenetic mark involved in gene transcription, DNA repair, and maintaining genomic stability.
• Aberrant H3K36 methylation is implicated in human developmental disorders and various cancers, underscoring its significance in health and disease.

Purpose of the Study:

• To consolidate current findings on H3K36 methylation regulation.
• To provide structural insights into the conversion of H3K36 dimethylation (H3K36me2) to H3K36 trimethylation (H3K36me3).
• To discuss the interplay between H3K36me and other epigenetic modifications.

Main Methods:

• Structural analysis of H3K36 methyltransferases and nucleosome interactions.
• Review and consolidation of existing literature on H3K36me regulation.
• Analysis of cis-acting factors binding to H3K36me marks.

Main Results:

• Nucleosomal components, including linker DNA and histone patches, alongside the H3 tail, are key determinants of H3K36 methylation.
• H3K36 methyltransferases (NSD2, NSD3, Set2/SETD2) precisely regulate H3K36me2 and H3K36me3 levels through nucleosome interaction and auto-inhibitory mechanisms.
• Specific structural features and cis-acting factors dictate the functional outcomes of H3K36me2 and H3K36me3.

Conclusions:

• Understanding the structural basis of H3K36 methylation is crucial for deciphering its role in development and disease.
• The conversion between H3K36me2 and H3K36me3 is tightly regulated and influenced by chromatin context.
• H3K36me cooperates with other epigenetic marks, such as H3K27me3, H3 acetylation, DNA methylation, and RNA modifications, to orchestrate complex epigenomic functions.