RT Journal Article
SR Electronic
T1 The JAK2-STAT pathway epigenetically regulates tolerized genes during the first encounter with bacterial antigens
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.10.16.342717
DO 10.1101/2020.10.16.342717
A1 Clara Lorente-Sorolla
A1 Octavio Morante-Palacios
A1 Antonio Garcia-Gomez
A1 Laura Ciudad
A1 Francesc Català-Moll
A1 Adolfo Ruiz-Sanmartín
A1 Mónica Martínez-Gallo
A1 Ricard Ferrer-Roca
A1 Juan Carlos Ruiz-Rodriguez
A1 Damiana Álvarez-Errico
A1 Esteban Ballestar
YR 2020
UL http://biorxiv.org/content/early/2020/10/17/2020.10.16.342717.abstract
AB Microbial challenges, such as widespread bacterial infection, induce endotoxin tolerance. This state of hyporesponsiveness to subsequent infections is mainly displayed by monocytes and macrophages. Endotoxin tolerance is generally acquired following a septic episode. In this study, we investigated DNA methylation changes during the acquisition of in vitro tolerance. We identified a set of TET2-mediated demethylation events that are specific to toll-like receptor (TLR) 2 and TLR4 stimulation. Lipopolysaccharide (LPS)-specific demethylation occurs at genomic sites that have low accessibility in quiescent monocytes, concomitantly with the transcriptional activation of many inflammation-related genes, and they are enriched in binding motifs for several signal transducer and activator of transcription (STAT) family members. Indeed, STAT1, STAT3 and STAT5, elements of the JAK2 pathway, are phosphorylated in association with the acquisition of endotoxin tolerance. Inhibition of the JAK2 pathway impairs the activation of tolerized genes on the first encounter with LPS. This is evidence of a crucial role for this pathway in determining the initial response of these genes to bacterial antigens and provides a pharmacological target to prevent exacerbated responses, allowing regulated responses upon subsequent challenges. Finally, we assess the pathological relevance of the JAK2 pathway in monocytes from patients with sepsis.Competing Interest StatementThe authors have declared no competing interest.