Dataset Information

Epigenetic regulation of transcription factor binding motifs promotes Th1 response in Chagas disease cardiomyopathy.

ABSTRACT: Chagas disease, caused by the protozoan Trypanosoma cruzi, is an endemic parasitic disease of Latin America, affecting 7 million people. Although most patients are asymptomatic, 30% develop complications, including the often-fatal Chronic Chagasic Cardiomyopathy (CCC). Although previous studies have demonstrated some genetic deregulations associated with CCCs, the causes of their deregulations remain poorly described. Based on bulk RNA-seq and whole genome DNA methylation data, we investigated the genetic and epigenetic deregulations present in the moderate and severe stages of CCC. Analysis of heart tissue gene expression profile allowed us to identify 1407 differentially expressed transcripts (DEGs) specific from CCC patients. A tissue DNA methylation analysis done on the same tissue has permitted the identification of 92 regulatory Differentially Methylated Regions (DMR) localized in the promoter of DEGs. An in-depth study of the transcription factors binding sites (TFBS) in the DMRs corroborated the importance of TFBS's DNA methylation for gene expression in CCC myocardium. TBX21, RUNX3 and EBF1 are the transcription factors whose binding motif appears to be affected by DNA methylation in the largest number of genes. By combining both transcriptomic and methylomic analysis on heart tissue, and methylomic analysis on blood, 4 biological processes affected by severe CCC have been identified, including immune response, ion transport, cardiac muscle processes and nervous system. An additional study on blood methylation of moderate CCC samples put forward the importance of ion transport and nervous system in the development of the disease.

SUBMITTER: Brochet P

PROVIDER: S-EPMC9441916 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Epigenetic regulation of transcription factor binding motifs promotes Th1 response in Chagas disease cardiomyopathy.

Brochet Pauline P Ianni Barbara Maria BM Laugier Laurie L Frade Amanda Farage AF Silva Nunes João Paulo JP Teixeira Priscila Camillo PC Mady Charles C Ferreira Ludmila Rodrigues Pinto LRP Ferré Quentin Q Santos Ronaldo Honorato Barros RHB Kuramoto Andreia A Cabantous Sandrine S Steffen Samuel S Stolf Antonio Noedir AN Pomerantzeff Pablo P Fiorelli Alfredo Inacio AI Bocchi Edimar Alcides EA Pissetti Cristina Wide CW Saba Bruno B Cândido Darlan da Silva DDS Dias Fabrício C FC Sampaio Marcelo Ferraz MF Gaiotto Fabio Antônio FA Marin-Neto José Antonio JA Fragata Abílio A Zaniratto Ricardo Costa Fernandes RCF Siqueira Sergio S Peixoto Giselle De Lima GL Rigaud Vagner Oliveira-Carvalho VO Bacal Fernando F Buck Paula P Almeida Rafael Ribeiro RR Lin-Wang Hui Tzu HT Schmidt André A Martinelli Martino M Hirata Mario Hiroyuki MH Donadi Eduardo Antonio EA Costa Pereira Alexandre A Rodrigues Junior Virmondes V Puthier Denis D Kalil Jorge J Spinelli Lionel L Cunha-Neto Edecio E Chevillard Christophe C

Frontiers in immunology 20220822

Chagas disease, caused by the protozoan <i>Trypanosoma cruzi</i>, is an endemic parasitic disease of Latin America, affecting 7 million people. Although most patients are asymptomatic, 30% develop complications, including the often-fatal Chronic Chagasic Cardiomyopathy (CCC). Although previous studies have demonstrated some genetic deregulations associated with CCCs, the causes of their deregulations remain poorly described. Based on bulk RNA-seq and whole genome DNA methylation data, we investi ...[more]

PMID: 36072583

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Project description:BackgroundClassically, models of DNA-transcription factor binding sites (TFBSs) have been based on relatively few known instances and have treated them as sites of fixed length using position weight matrices (PWMs). Various extensions to this model have been proposed, most of which take account of dependencies between the bases in the binding sites. However, some transcription factors are known to exhibit some flexibility and bind to DNA in more than one possible physical configuration. In some cases this variation is known to affect the function of binding sites. With the increasing volume of ChIP-seq data available it is now possible to investigate models that incorporate this flexibility. Previous work on variable length models has been constrained by: a focus on specific zinc finger proteins in yeast using restrictive models; a reliance on hand-crafted models for just one transcription factor at a time; and a lack of evaluation on realistically sized data sets.ResultsWe re-analysed binding sites from the TRANSFAC database and found motivating examples where our new variable length model provides a better fit. We analysed several ChIP-seq data sets with a novel motif search algorithm and compared the results to one of the best standard PWM finders and a recently developed alternative method for finding motifs of variable structure. All the methods performed comparably in held-out cross validation tests. Known motifs of variable structure were recovered for p53, Stat5a and Stat5b. In addition our method recovered a novel generalised version of an existing PWM for Sp1 that allows for variable length binding. This motif improved classification performance.ConclusionsWe have presented a new gapped PWM model for variable length DNA binding sites that is not too restrictive nor over-parameterised. Our comparison with existing tools shows that on average it does not have better predictive accuracy than existing methods. However, it does provide more interpretable models of motifs of variable structure that are suitable for follow-up structural studies. To our knowledge, we are the first to apply variable length motif models to eukaryotic ChIP-seq data sets and consequently the first to show their value in this domain. The results include a novel motif for the ubiquitous transcription factor Sp1.

Dataset Information

Epigenetic regulation of transcription factor binding motifs promotes Th1 response in Chagas disease cardiomyopathy.

Publications

Epigenetic regulation of transcription factor binding motifs promotes Th1 response in Chagas disease cardiomyopathy.

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