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Genome-wide chromatin interaction map for Trypanosoma cruzi.

ABSTRACT: Trypanosomes are eukaryotic, unicellular parasites, such as Trypanosoma brucei, which causes sleeping sickness, and Trypanosoma cruzi, which causes Chagas disease. Genomes of these parasites comprise core regions and species-specific disruptive regions that encode multigene families of surface glycoproteins. Few transcriptional regulators have been identified in these parasites, and the role of spatial organization of the genome in gene expression is unclear. Here we mapped genome-wide chromatin interactions in T. cruzi using chromosome conformation capture (Hi-C), and we show that the core and disruptive regions form three-dimensional chromatin compartments named C and D. These chromatin compartments differ in levels of DNA methylation, nucleosome positioning and chromatin interactions, affecting genome expression dynamics. Our data reveal that the trypanosome genome is organized into chromatin-folding domains and transcription is affected by the local chromatin structure. We propose a model in which epigenetic mechanisms affect gene expression in trypanosomes.

SUBMITTER: Diaz-Viraque F

PROVIDER: S-EPMC10627812 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Genome-wide chromatin interaction map for Trypanosoma cruzi.

Díaz-Viraqué Florencia F Chiribao María Laura ML Libisch María Gabriela MG Robello Carlos C

Nature microbiology 20231012 11

Trypanosomes are eukaryotic, unicellular parasites, such as Trypanosoma brucei, which causes sleeping sickness, and Trypanosoma cruzi, which causes Chagas disease. Genomes of these parasites comprise core regions and species-specific disruptive regions that encode multigene families of surface glycoproteins. Few transcriptional regulators have been identified in these parasites, and the role of spatial organization of the genome in gene expression is unclear. Here we mapped genome-wide chromatin ...[more]

PMID: 37828247

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Project description:BackgroundFamilial aggregation of Chagas cardiac disease in T. cruzi-infected persons suggests that human genetic variation may be an important determinant of disease progression.ObjectiveTo perform a GWAS using a well-characterized cohort to detect single nucleotide polymorphisms (SNPs) and genes associated with cardiac outcomes.MethodsA retrospective cohort study was developed by the NHLBI REDS-II program in Brazil. Samples were collected from 499 T. cruzi seropositive blood donors who had donated between 1996 and 2002, and 101 patients with clinically diagnosed Chagas cardiomyopathy. In 2008-2010, all subjects underwent a complete medical examination. After genotype calling, quality control filtering with exclusion of 20 cases, and imputation of 1,000 genomes variants; association analysis was performed for 7 cardiac and parasite related traits, adjusting for population stratification.ResultsThe cohort showed a wide range of African, European, and modest Native American admixture proportions, consistent with the recent history of Brazil. No SNPs were found to be highly (P<10(-8)) associated with cardiomyopathy. The two mostly highly associated SNPs for cardiomyopathy (rs4149018 and rs12582717; P-values <10(-6)) are located on Chromosome 12p12.2 in the SLCO1B1 gene, a solute carrier family member. We identified 44 additional genic SNPs associated with six traits at P-value <10(-6): Ejection Fraction, PR, QRS, QT intervals, antibody levels by EIA, and parasitemia by PCR.ConclusionThis GWAS identified suggestive SNPs that may impact the risk of progression to cardiomyopathy. Although this Chagas cohort is the largest examined by GWAS to date, (580 subjects), moderate sample size may explain in part the limited number of significant SNP variants. Enlarging the current sample through expanded cohorts and meta-analyses, and targeted studies of candidate genes, will be required to confirm and extend the results reported here. Future studies should also include exposed seronegative controls to investigate genetic associations with susceptibility or resistance to T. cruzi infection and non-Chagas cardiomyopathy.

Project description:BackgroundTrypanosoma cruzi, the causal agent of Chagas Disease, affects more than 16 million people in Latin America. The clinical outcome of the disease results from a complex interplay between environmental factors and the genetic background of both the human host and the parasite. However, knowledge of the genetic diversity of the parasite, is currently limited to a number of highly studied loci. The availability of a number of genomes from different evolutionary lineages of T. cruzi provides an unprecedented opportunity to look at the genetic diversity of the parasite at a genomic scale.ResultsUsing a bioinformatic strategy, we have clustered T. cruzi sequence data available in the public domain and obtained multiple sequence alignments in which one or two alleles from the reference CL-Brener were included. These data covers 4 major evolutionary lineages (DTUs): TcI, TcII, TcIII, and the hybrid TcVI. Using these set of alignments we have identified 288,957 high quality single nucleotide polymorphisms and 1,480 indels. In a reduced re-sequencing study we were able to validate ~ 97% of high-quality SNPs identified in 47 loci. Analysis of how these changes affect encoded protein products showed a 0.77 ratio of synonymous to non-synonymous changes in the T. cruzi genome. We observed 113 changes that introduce or remove a stop codon, some causing significant functional changes, and a number of tri-allelic and tetra-allelic SNPs that could be exploited in strain typing assays. Based on an analysis of the observed nucleotide diversity we show that the T. cruzi genome contains a core set of genes that are under apparent purifying selection. Interestingly, orthologs of known druggable targets show statistically significant lower nucleotide diversity values.ConclusionsThis study provides the first look at the genetic diversity of T. cruzi at a genomic scale. The analysis covers an estimated ~ 60% of the genetic diversity present in the population, providing an essential resource for future studies on the development of new drugs and diagnostics, for Chagas Disease. These data is available through the TcSNP database (http://snps.tcruzi.org).

Project description:BackgroundCCCH type zinc finger proteins are RNA binding proteins with regulatory functions at all stages of mRNA metabolism. The best-characterized member, tritetraproline (TTP), binds to AU rich elements in 3' UTRs of unstable mRNAs, mediating their degradation. In kinetoplastids, CCCH type zinc finger proteins have been identified as being involved in the regulation of the life cycle and possibly the cell cycle. To date, no systematic listing of CCCH proteins in kinetoplastids is available.ResultsWe have identified the complete set of CCCH type zinc finger proteins in the available genomes of the kinetoplastid protozoa Trypanosoma brucei, Trypanosoma cruzi and Leishmania major. One fifths (20%) of all CCCH motifs fall into non-conventional classes and many had not been previously identified. One third of all CCCH proteins have more than one CCCH motif, suggesting multivalent RNA binding. One third have additional recognizable domains. The vast majority are unique to Kinetoplastida or to a subgroup within. Two exceptions are of interest: the putative orthologue of the mRNA nuclear export factor Mex67 and a 3'-5' exoribonuclease restricted to Leishmania species. CCCH motifs are absent from these proteins in other organisms and might be unique, novel features of the Kinetoplastida homologues. Of the others, several have a predicted, and in one case experimentally confirmed, connection to the ubiquitination pathways, for instance a HECT-type E3 ubiquitin ligase. The total number of kinetoplastid CCCH proteins is similar to the number in higher eukaryotes but lower than in yeast. A comparison of the genomic loci between the Trypanosomatidae homologues provides insight into both the evolution of the CCCH proteins as well as the CCCH motifs.ConclusionThis study provides the first systematic listing of the Kinetoplastida CCCH proteins. The number of CCCH proteins with more then one CCCH motif is larger than previously estimated, due to the identification of non-conventional CCCH motifs. Experimental approaches are now necessary to examine the functions of the many unique CCCH proteins as well as the function of the putative Mex67 and the Leishmania 3'-5' exoribonuclease.

Dataset Information

Genome-wide chromatin interaction map for Trypanosoma cruzi.

Publications

Genome-wide chromatin interaction map for Trypanosoma cruzi.

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