AUTHOR=Brochet Pauline , Ianni Barbara Maria , Laugier Laurie , Frade Amanda Farage , Silva Nunes João Paulo , Teixeira Priscila Camillo , Mady Charles , Ferreira Ludmila Rodrigues Pinto , Ferré 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 , Cândido Darlan da Silva , Dias Fabrício C. , Sampaio Marcelo Ferraz , Gaiotto Fabio Antônio , Marin-Neto José Antonio , Fragata Abílio , 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 André , 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 TITLE=Epigenetic regulation of transcription factor binding motifs promotes Th1 response in Chagas disease cardiomyopathy JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.958200 DOI=10.3389/fimmu.2022.958200 ISSN=1664-3224 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.