MLL1 is regulated by KSHV LANA and is important for virus latency

Area of Science:

• Epigenetics
• Virology
• Molecular Biology

Background:

• Mixed lineage leukemia 1 (MLL1) is a histone methyltransferase.
• Kaposi's sarcoma-associated herpesvirus (KSHV) is a major cause of malignancy in AIDS patients.
• KSHV establishes latent infections characterized by epigenetic modifications on its genome.

Purpose of the Study:

• To investigate the role of MLL1 in KSHV latency.
• To elucidate the interaction between KSHV LANA and MLL1.
• To determine the structural basis of LANA-MLL1 interaction.

Main Methods:

• Co-immunoprecipitation to assess protein interactions.
• Chromatin immunoprecipitation to detect epigenetic modifications.
• X-ray crystallography to determine protein structure.
• Viral latency assays to evaluate MLL1 function.

Main Results:

• KSHV LANA recruits MLL1 to viral DNA, establishing H3K4me3 marks at terminal repeat elements.
• LANA interacts with MLL1 complex members, including WDR5, and regulates MLL1 activity.
• The crystal structure reveals a LANA-WDR5 interaction, suggesting a regulatory mechanism.
• MLL1 disruption severely impairs KSHV latency establishment, a phenotype rescued by active MLL1.

Conclusions:

• MLL1 plays a critical, regulable role in KSHV infection establishment.
• LANA-mediated recruitment and regulation of MLL1 are central to KSHV latency.
• MLL1 represents a potential therapeutic target for KSHV-associated malignancies.
• Non-host factors can regulate MLL1, suggesting broader implications for epigenetic regulation.