Gene activation precedes DNA demethylation in response to infection in human dendritic cells

Alain Pacis (1, 2) , Florence Mailhot-Léonard (1, 2) , Ludovic Tailleux (3, 4) , Haley Randolph (1, 2) , Vania Yotova (1) , Anne Dumaine (1) , Jean-Christophe Grenier (1) , Luis B. Barreiro (1, 5, 6)

1 Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada]
2 Département de Biochimie et Médecine Moléculaire [UdeM-Montréal]
3 Génétique mycobactérienne - Mycobacterial genetics
4 Pathogénomique mycobactérienne intégrée - Integrated Mycobacterial Pathogenomics
5 UdeM - Université de Montréal
6 University of Chicago

DNA methylation is considered to be a relatively stable epigenetic mark. However, a growing body of evidence indicates that DNA methylation levels can change rapidly; for example, in innate immune cells facing an infectious agent. Nevertheless, the causal relationship between changes in DNA methylation and gene expression during infection remains to be elucidated. Here, we generated time-course data on DNA methylation, gene expression, and chromatin accessibility patterns during infection of human dendritic cells with Mycobacterium tuberculosis We found that the immune response to infection is accompanied by active demethylation of thousands of CpG sites overlapping distal enhancer elements. However, virtually all changes in gene expression in response to infection occur before detectable changes in DNA methylation, indicating that the observed losses in methylation are a downstream consequence of transcriptional activation. Footprinting analysis revealed that immune-related transcription factors (TFs), such as NF-κB/Rel, are recruited to enhancer elements before the observed losses in methylation, suggesting that DNA demethylation is mediated by TF binding to cis-acting elements. Collectively, our results show that DNA demethylation plays a limited role to the establishment of the core regulatory program engaged upon infection.

Keywords: DNA methylation; dendritic cells; epigenetic; immune responses; tuberculosis

Domains: Life Sciences [q-bio]; Genetics; Human genetics; Immunology; Innate immunity

Alain Pacis, Florence Mailhot-Léonard, Ludovic Tailleux, Haley Randolph, Vania Yotova, et al.. Gene activation precedes DNA demethylation in response to infection in human dendritic cells. Proceedings of the National Academy of Sciences of the United States of America, 2019, 116 (14), pp.6938-6943. ⟨10.1073/pnas.1814700116⟩. ⟨pasteur-02876157⟩