The VEXing problem of monoallelic expression in the African trypanosome

Schulz, Danae; Papavasiliou, F. Nina

doi:10.1073/pnas.1608546113

Cited by 2 publications

(2 citation statements)

References 20 publications

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“…Using both bulk RNA-Seq and proteomic analysis of cell-surface VSGs, we detected transcripts and proteins from all VSG -ESs, confirming that the transcribed VSG genes yielded proteins that were delivered to the cell surface 19 . Whether VSG genes were being derepressed simultaneously or individually in single cells remained unclear, however, due to the limitations of population-based analyses 33 . We addressed this question using single-cell transcriptomics.…”

Section: Discussionmentioning

confidence: 99%

An allele-selective inter-chromosomal protein bridge supports monogenic antigen expression in the African trypanosome

Faria,

Tinti,

Marques

et al. 2023

Nat Commun

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UPF1-like helicases play roles in telomeric heterochromatin formation and X-chromosome inactivation, and also in monogenic variant surface glycoprotein (VSG) expression via VSG exclusion-factor-2 (VEX2), a UPF1-related protein in the African trypanosome. We show that VEX2 associates with chromatin specifically at the single active VSG expression site on chromosome 6, forming an allele-selective connection, via VEX1, to the trans-splicing locus on chromosome 9, physically bridging two chromosomes and the VSG transcription and splicing compartments. We further show that the VEX-complex is multimeric and self-regulates turnover to tightly control its abundance. Using single cell transcriptomics following VEX2-depletion, we observed simultaneous derepression of many other telomeric VSGs and multi-allelic VSG expression in individual cells. Thus, an allele-selective, inter-chromosomal, and self-limiting VEX1-2 bridge supports monogenic VSG expression and multi-allelic VSG exclusion.

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Section: Discussionmentioning

confidence: 99%

An allele-selective inter-chromosomal protein bridge supports monogenic antigen expression in the African trypanosome

Faria,

Tinti,

Marques

et al. 2023

Nat Commun

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“…Thus, VSG transcription and mRNA splicing take place within a specific compartment of the nucleus and are associated closely with VEX1 and VEX2 proteins ( Figure 2 ) ( Faria et al, 2021 ). The coalescence of the VEX1-bound splice leader locus and the VEX2-bound BES into the expression site body may serve to activate Pol I transcription and subsequently induce repression of the remaining BESs ( Glover et al, 2016 ; Schulz and Papavasiliou, 2016 ; Cestari and Stuart, 2018 ; Faria et al, 2021 ). Transcription-mediated gene silencing is a hallmark of heterochromatinization in other stochastic systems such as yeast mating-type switching, and could be involved in olfactory receptor heterochromatinization as well ( Allshire and Madhani, 2018 ).…”

Section: Variant Surface Glycoproteinsmentioning

confidence: 99%

May the Odds Be Ever in Your Favor: Non-deterministic Mechanisms Diversifying Cell Surface Molecule Expression

Williams

Sikora

Hammer

et al. 2022

Front. Cell Dev. Biol.

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How does the information in the genome program the functions of the wide variety of cells in the body? While the development of biological organisms appears to follow an explicit set of genomic instructions to generate the same outcome each time, many biological mechanisms harness molecular noise to produce variable outcomes. Non-deterministic variation is frequently observed in the diversification of cell surface molecules that give cells their functional properties, and is observed across eukaryotic clades, from single-celled protozoans to mammals. This is particularly evident in immune systems, where random recombination produces millions of antibodies from only a few genes; in nervous systems, where stochastic mechanisms vary the sensory receptors and synaptic matching molecules produced by different neurons; and in microbial antigenic variation. These systems employ overlapping molecular strategies including allelic exclusion, gene silencing by constitutive heterochromatin, targeted double-strand breaks, and competition for limiting enhancers. Here, we describe and compare five stochastic molecular mechanisms that produce variety in pathogen coat proteins and in the cell surface receptors of animal immune and neuronal cells, with an emphasis on the utility of non-deterministic variation.

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The VEXing problem of monoallelic expression in the African trypanosome

Cited by 2 publications

References 20 publications

An allele-selective inter-chromosomal protein bridge supports monogenic antigen expression in the African trypanosome

An allele-selective inter-chromosomal protein bridge supports monogenic antigen expression in the African trypanosome

May the Odds Be Ever in Your Favor: Non-deterministic Mechanisms Diversifying Cell Surface Molecule Expression

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