Frontiers in Immunology (Aug 2022)

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

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

DOI
https://doi.org/10.3389/fimmu.2022.958200
Journal volume & issue
Vol. 13

Abstract

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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.

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