A heterochromatin inducing protein differentially recognizes self versus foreign genomes

Area of Science:

• Molecular Biology
• Virology
• Epigenetics

Background:

• Krüppel-associated box-domain zinc finger proteins (KRAB-ZFPs) are transcriptional repressors that silence genomes.
• KRAB-ZFPs recruit TRIM28/KAP1 to heterochromatinize host DNA and suppress foreign genetic elements.
• The mechanism by which KRAB-ZFPs recognize target sequences in host versus foreign genomes remains largely unknown.

Purpose of the Study:

• To investigate how the KRAB-ZFP, SZF1, recognizes target sequences in both the host genome and the Epstein-Barr virus (EBV) genome.
• To understand the role of SZF1 in maintaining EBV latency in B-lymphocytes.

Main Methods:

• In situ footprint mapping was performed on both viral and host genomes in B-lymphocytes harboring latent or replicative EBV.
• Virus mutagenesis studies were conducted to assess the importance of identified binding sites.

Main Results:

• SZF1 recognizes the host genome via a repeat sequence-bearing motif near centromeres.
• SZF1 utilizes distinct, non-homologous binding sites on the EBV genome to silence lytic/replicative genes.
• These distinct EBV binding sites are crucial for establishing and maintaining viral latency and silencing newly infected cells.
• SZF1 does not target these viral binding sites on the human genome, indicating differential recognition strategies.

Conclusions:

• SZF1 employs distinct target recognition mechanisms for host and viral genomes.
• This differential binding strategy allows for the regulation of persistent viral invaders without compromising host genome stability.
• The findings reveal a sophisticated host defense mechanism against viral genomes like EBV.