Monoallelic expression and epigenetic inheritance sustained by a Trypanosoma brucei variant surface glycoprotein exclusion complex

• Published in: Nature communications Vol. 10; no. 1; pp. 3023 - 14
• Main Authors: Faria, Joana, Glover, Lucy, Hutchinson, Sebastian, Boehm, Cordula, Field, Mark C., Horn, David
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.07.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 14/19; 38/15; 38/23; 38/89; 38/91; 631/1647/2210; 631/208/176/2016; 631/326/417/1716; 631/326/417/2550; 82/58; Alleles; Allelic exclusion; Animals; Antigenic Variation; Antigenic Variation - genetics; Antigenic Variation - immunology; Antigens; Cell Line; Chromatin Assembly Factor-1; Chromatin Assembly Factor-1 - immunology; Chromatin Assembly Factor-1 - metabolism; Chromatin remodeling; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA helicase; DNA Replication; DNA Replication - immunology; DNA-directed RNA polymerase; Epigenesis, Genetic; Epigenesis, Genetic - immunology; Epigenetics; Eukaryotes; Gene Expression Regulation; Gene Expression Regulation - immunology; Gene families; Glycoproteins; Heredity; Host-Parasite Interactions; Host-Parasite Interactions - genetics; Host-Parasite Interactions - immunology; Humanities and Social Sciences; Immune Evasion; Life Sciences; multidisciplinary; Parasites; Proteins; Protozoa; Protozoan Proteins; Protozoan Proteins - genetics; Protozoan Proteins - immunology; Replication; RNA polymerase; Science; Science (multidisciplinary); Transcription; Transcription, Genetic; Transcription, Genetic - immunology; Trypanosoma brucei; Trypanosoma brucei brucei; Trypanosoma brucei brucei - genetics; Trypanosoma brucei brucei - immunology; Trypanosomiasis, African; Trypanosomiasis, African - immunology; Trypanosomiasis, African - parasitology; Variant surface glycoprotein; Variant Surface Glycoproteins, Trypanosoma; Variant Surface Glycoproteins, Trypanosoma - genetics; Variant Surface Glycoproteins, Trypanosoma - immunology; Variant Surface Glycoproteins, Trypanosoma - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10823-8

The largest gene families in eukaryotes are subject to allelic exclusion, but mechanisms underpinning single allele selection and inheritance remain unclear. Here, we describe a protein complex sustaining variant surface glycoprotein ( VSG ) allelic exclusion and antigenic variation in Trypanosoma brucei parasites. The VSG- exclusion-1 (VEX1) protein binds both telomeric VSG -associated chromatin and VEX2, an ortholog of nonsense-mediated-decay helicase, UPF1. VEX1 and VEX2 assemble in an RNA polymerase-I transcription-dependent manner and sustain the active, subtelomeric VSG -associated transcription compartment. VSG transcripts and VSG coats become highly heterogeneous when VEX proteins are depleted. Further, the DNA replication-associated chromatin assembly factor, CAF-1, binds to and specifically maintains VEX1 compartmentalisation following DNA replication. Thus, the VEX-complex controls VSG -exclusion, while CAF-1 sustains VEX-complex inheritance in association with the active- VSG . Notably, the VEX2-orthologue and CAF-1 in mammals are also implicated in exclusion and inheritance functions. In trypanosomes, these factors sustain a highly effective and paradigmatic immune evasion strategy. Monoallelic expression of variant surface glycoprotein genes ( VSGs ) is essential for immune evasion by Trypanosoma brucei . Here, Faria et al . show that the VEX protein complex controls VSG allelic exclusion, and that CAF‐1 sustains inheritance of the VEX‐complex in association with the active VSG .