Identification of the ISWI Chromatin Remodeling Complex of the Early Branching Eukaryote Trypanosoma brucei

Stanne, Tara M.; Narayanan, Mani Shankar; Ridewood, Sophie; Ling, Alexandra; Witmer, Kathrin; Kushwaha, Manish; Wiesler, Simone C.; Wickstead, Bill; Wood, Jennifer; Rudenko, Gloria

doi:10.1074/jbc.m115.679019

Cited by 21 publications

(39 citation statements)

References 85 publications

(139 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Knockdown of histone H3 variant (H3V) or bromodomain factor 3 (BDF3) results in transcription of ESs and subtelomeric array VSGs, whereas BDF2 null cells transcribe VSG genes from silent ESs (12,34). Knockdown of the ISWI chromatin remodeling complex, which is enriched at ES promoter regions, rRNA loci, and SSRs, also affects transcription of silent ESs but not of VSG genes (11,35). PIP5Pase may have functional associations with some of these proteins, which control transcription of VSG genes from ESs and subtelomeric arrays, as some of these proteins were also found to interact with PIP5Pase and/or RAP1 (discussed below).…”

Section: Discussionmentioning

confidence: 99%

Nuclear Phosphatidylinositol 5-Phosphatase Is Essential for Allelic Exclusion of Variant Surface Glycoprotein Genes in Trypanosomes

Cestari

McLeland-Wieser

Stuart

2019

Molecular and Cellular Biology

View full text Add to dashboard Cite

Allelic exclusion of variant surface glycoprotein (VSG) genes is essential for African trypanosomes to evade the host antibody response by antigenic variation. The mechanisms by which this parasite expresses only one of its ∼2,000 VSG genes at a time are unknown. We show that nuclear phosphatidylinositol 5-phosphatase (PIP5Pase) interacts with repressor activator protein 1 (RAP1) in a multiprotein complex and functions in the control of VSG allelic exclusion. RAP1 binds PIP5Pase substrate phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], and catalytic mutation of PIP5Pase that inhibits PI(3,4,5)P3 dephosphorylation results in simultaneous transcription of VSGs from all telomeric expression sites (ESs) and from silent subtelomeric VSG arrays. PIP5Pase and RAP1 bind to telomeric ESs, especially at 70-bp repeats and telomeres, and their binding is altered by PIP5Pase inactivation or knockdown, implying changes in ES chromatin organization. Our data suggest a model whereby PIP5Pase controls PI(3,4,5)P3 binding by RAP1 and, thus, RAP1 silencing of telomeric and subtelomeric VSG genes. Hence, allelic exclusion of VSG genes may entail control of nuclear phosphoinositides.

show abstract

Section: Discussionmentioning

confidence: 99%

Nuclear Phosphatidylinositol 5-Phosphatase Is Essential for Allelic Exclusion of Variant Surface Glycoprotein Genes in Trypanosomes

Cestari

McLeland-Wieser

Stuart

2019

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…For example, a histone H3 variant, a bloodstream stagespecific modified DNA base known as J or hydroxymethyluracil (22,23), the chromatin remodeling ISWI complex (24), the histone H3K76 trimethyltransferase DOT1B (25), and the telomere-associated protein RAP1 (26) all facilitate VSG-ES silencing. In addition, cohesin function facilitates maintenance of the active VSG-ES (27), and inositol phosphate signaling impacts VSG-ES regulation (28).…”

mentioning

confidence: 99%

VEX1 controls the allelic exclusion required for antigenic variation in trypanosomes

Glover

Hutchinson

Alsford

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

184

View full text Add to dashboard Cite

Allelic exclusion underpins antigenic variation and immune evasion in African trypanosomes. These bloodstream parasites use RNA polymerase-I (pol-I) to transcribe just one telomeric variant surface glycoprotein (VSG) gene at a time, producing superabundant and switchable VSG coats. We identified trypanosome VSG exclusion-1 (VEX1) using a genetic screen for defects in telomere-exclusive expression. VEX1 was sequestered by the active VSG and silencing of other VSGs failed when VEX1 was either ectopically expressed or depleted, indicating positive and negative regulation, respectively. Positive regulation affected VSGs and nontelomeric pol-I-transcribed genes, whereas negative regulation primarily affected VSGs. Negative regulation by VEX1 also affected telomeric pol-I-transcribed reporter constructs, but only when they contained blocks of sequence sharing homology with a pol-I-transcribed locus. We conclude that restricted positive regulation due to VEX1 sequestration, combined with VEX1-dependent, possibly homology-dependent silencing, drives a "winner-takes-all" mechanism of allelic exclusion.epigenetic | monoallelic | silencing | telomere | Trypanosoma brucei C ells often restrict expression to a single allele of a gene or gene family. This allelic exclusion underpins antigenic variation in pathogens, including trypanosomes that cause sleeping sickness (1) and Plasmodium parasites that cause malaria (2). Allelic exclusion is also essential for singular olfactory receptor expression and a sense of smell in metazoa (3). Although many factors have been identified that are required for the expression of one allele or for the silencing of other alleles in these systems, our understanding of the mechanisms by which expression and silencing are established and coordinated remains incomplete (1-3).The African trypanosome Trypanosoma brucei is a flagellated parasitic protozoan transmitted among mammalian hosts by tsetse flies. In addition to causing trypanosomiasis in humans, a fatal and neglected tropical disease, these parasites also cause nagana in cattle. Antigenic variation is essential for persistent bloodstream infection in the face of host adaptive immune defenses and has long been a paradigm for studies on allelic exclusion (1); parasite immune evasion depends upon singular variant surface glycoprotein (VSG) gene expression and VSG switching. Although multiple subtelomeric VSGs are available for expression (4), only one is transcribed (5). Both active and silent VSGs are located at the ends of polycistronic transcription units known as expression sites (ESs) (6). Notably, VSG-ES promoters (6) recruit RNA polymerase-I (pol-I) that typically transcribes ribosomal RNA genes (7). Indeed, the active VSG-ES is associated with an extranucleolar focus of pol-I known as the expression-site body (ESB) (8-10). Although the active VSG-ES is specifically depleted of nucleosomes (11, 12), silent VSG-ESs are similarly located in the extranucleolar space in bloodstream-form cells, and neither active nor silent VSG-ESs show an ...

show abstract

“…Up to now, transcriptional control seemed to be no relevant in trypanosomes. However, recently, several reports implicated various proteins in RNA Pol I and Pol III transcription regulation (Romero-Meza et al 2017;Stanne et al 2015), while little is known about the factors involved in transcriptional regulation of Pol II-driven genes. Interestingly, it has been shown that the spatial position of genes within a PTU can have a major impact in the control of gene expression.…”

Section: Discussionmentioning

confidence: 99%

The Trypanosoma brucei RNA‐Binding Protein TbRRM1 is Involved in the Transcription of a Subset of RNA Pol II‐Dependent Genes

Bañuelos

Levy

Níttolo

et al. 2019

J Eukaryotic Microbiology

View full text Add to dashboard Cite

It has been long thought that RNA Polymerase (Pol) II transcriptional regulation does not operate in trypanosomes. However, recent reports have suggested that these organisms could regulate RNA Pol II transcription by epigenetic mechanisms. In this paper, we investigated the role of TbRRM1 in transcriptional regulation of RNA Pol II‐dependent genes by focusing both in genes located in a particular polycistronic transcription unit (PTU) and in the monocistronic units of the SL‐RNA genes. We showed that TbRRM1 is recruited throughout the PTU, with a higher presence on genes than intergenic regions. However, its depletion leads both to the decrease of nascent RNA and to chromatin compaction only of regions located distal to the main transcription start site. These findings suggest that TbRRM1 facilitates the RNA Pol II transcriptional elongation step by collaborating to maintain an open chromatin state in particular regions of the genome. Interestingly, the SL‐RNA genes do not recruit TbRRM1 and, after TbRRM1 knockdown, nascent SL‐RNAs accumulate while the chromatin state of these regions remains unchanged. Although it was previously suggested that TbRRM1 could regulate RNA Pol II‐driven genes, we provide here the first experimental evidence which involves TbRRM1 to transcriptional regulation.

show abstract

Identification of the ISWI Chromatin Remodeling Complex of the Early Branching Eukaryote Trypanosoma brucei

Cited by 21 publications

References 85 publications

Nuclear Phosphatidylinositol 5-Phosphatase Is Essential for Allelic Exclusion of Variant Surface Glycoprotein Genes in Trypanosomes

Nuclear Phosphatidylinositol 5-Phosphatase Is Essential for Allelic Exclusion of Variant Surface Glycoprotein Genes in Trypanosomes

VEX1 controls the allelic exclusion required for antigenic variation in trypanosomes

The Trypanosoma brucei RNA‐Binding Protein TbRRM1 is Involved in the Transcription of a Subset of RNA Pol II‐Dependent Genes

Contact Info

Product

Resources

About