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

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Brochet, Pauline ; Ianni, Barbara Maria ; Laugier, Laurie ; Frade, Amanda Farage ; Silva Nunes, Joao Paulo ; Teixeira, Priscila Camillo ; Mady, Charles ; Ferreira, Ludmila Rodrigues Pinto ; Ferre, Quentin ; Santos, Ronaldo Honorato Barros ; Kuramoto, Andreia ; Cabantous, Sandrine ; Steffen, Samuel ; Stolf, Antonio Noedir ; Pomerantzeff, Pablo ; Fiorelli, Alfredo Inacio ; Bocchi, Edimar Alcides ; Pissetti, Cristina Wide ; Saba, Bruno ; Candido, Darlan da Silva ; Dias, Fabricio C. ; Sampaio, Marcelo Ferraz ; Gaiotto, Fabio Antonio ; Marin-Neto, Jose Antonio ; Fragata, Abilio ; Zaniratto, Ricardo Costa Fernandes ; Siqueira, Sergio ; Peixoto, Giselle De Lima ; Rigaud, Vagner Oliveira-Carvalho ; Bacal, Fernando ; Buck, Paula ; Almeida, Rafael Ribeiro ; Lin-Wang, Hui Tzu ; Schmidt, Andre ; Martinelli, Martino ; Hirata, Mario Hiroyuki ; Donadi, Eduardo Antonio ; Costa Pereira, Alexandre ; Rodrigues Junior, Virmondes ; Puthier, Denis ; Kalil, Jorge ; Spinelli, Lionel ; Cunha-Neto, Edecio ; Chevillard, Christophe

• Document type: Journal article
• Source: FRONTIERS IN IMMUNOLOGY; v. 13, p. 16-pg., 2022-08-22.

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. (AU)

• FAPESP's process: 14/50890-5 - INCT of Investigation in Immunology
• Grantee: Jorge Elias Kalil Filho
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/50302-3 - Identification of predictive / prognostic genetic signature in Chagas cardiomyopathy: a systems biology approach
• Grantee: Edecio Cunha Neto
• Support Opportunities: Regular Research Grants