Open AccessTET1 is an important transcriptional activator of TNFα expression in macrophages
Author(s) -
Fangfang Sun,
Irene Abreu-Rodríguez,
Shuang Ye,
Oliver Distler,
Michel Neidhart,
Emmanuel Karouzakis
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0218551
Subject(s) - tumor necrosis factor alpha , inflammation , epigenetics , activator (genetics) , pathogenesis , biology , gene expression , chromosomal translocation , microbiology and biotechnology , regulation of gene expression , proinflammatory cytokine , cytokine , gene , immunology , cancer research , chemistry , genetics
Activation of macrophages and overexpression of TNFα is associated with the pathogenesis of chronic inflammatory diseases. However, the mechanisms leading to TNFα overexpression are still unknown. 5-methylocytosine (5-mC) is an epigenetic modification that is associated with silenced genes. Recent studies showed that it is converted to 5-hydroxylmethylocytosine (5-hmC) and reactivates gene expression through the action of the family of Ten-Eleven-Translocation (TET1-3) enzymes. In this study, we show that 5-hmC levels are increased globally and specifically in the TNFα promoter during the differentiation of monocytes to macrophages. In addition, the levels of 5-hmC are increased upon LPS stimulation of macrophages. Furthermore, CRIPSR stable knockout of TET1 decreases the expression of TNFα and other pro-inflammatory cytokines. In conclusion, we showed that TET1 contributes to the activation of macrophages possibly through regulation of 5-hydroxymethylation in the promoter of pro-inflammatory cytokine genes. The TET1 enzyme could be a promising therapeutic target to inhibit the persistent inflammation caused by macrophages in chronic inflammatory diseases.