RESUMO
The Polycomb group (PcG) proteins are chromatin factors underlying the process of transcriptional memory to preserve developmental decisions and keep cellular identities. However, not only developmental signals need to be memorized and thus maintained during the life of an organism. For host protection against pathogens, also a memory of previous exposures to an immunogenic stimulus is crucial to mount a more protective immune response upon re-exposure. The antigen-specific adaptive immunity in vertebrates is an example of such a memory to previous immunogenic stimulation. Recently, adaptive characteristics were also attributed to innate immunity, which was classically seen to lack memory. However, the mechanistic details of an adaptive innate immune response are yet to be fully understood and chromatin-based epigenetic mechanisms seem to play an important role in this phenomenon. Possibly, PcG proteins can contribute to such an epigenetic innate immune memory. In this study, we analyzed whether the PcG system can mediate a transcriptional memory of exposure to lipopolysaccharides (LPS). To this end, various forms of LPS pre-treatment were applied to reporter cells and expression kinetics of PcG target genes were analyzed after a second LPS exposure. Neither single nor multiple LPS pre-treatment affected the induction of endogenous LPS-responsive transcripts upon re-exposure. Altogether, our extensive analyses did not provide any evidence for a PcG system-mediated memory of LPS stimulation.
Assuntos
Memória Imunológica/genética , Proteínas do Grupo Polycomb/genética , Proteínas do Grupo Polycomb/imunologia , Imunidade Adaptativa/genética , Imunidade Adaptativa/imunologia , Animais , Linhagem Celular , Cromatina/genética , Drosophila/imunologia , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Epigênese Genética/genética , Imunidade Inata/genética , Imunidade Inata/imunologia , Memória Imunológica/imunologia , Lipopolissacarídeos/genética , Lipopolissacarídeos/imunologia , Proteínas do Grupo Polycomb/metabolismoRESUMO
Inducible gene expression underlies the epigenetically inherited differentiation program of most immune cells. We report that the promoter of the FOXP3 gene possesses two distinct functional states: an "off state" mediated by the polycomb histone methyltransferase complex and a histone acetyltransferase-dependent "on state." Regulating these states is the presence of a Kruppel-like factor (KLF)-containing Polycomb response element. In the KLF10(-/-) mouse, the FOXP3 promoter is epigenetically silenced by EZH2 (Enhancer of Zeste 2)-mediated trimethylation of Histone 3 K27; thus, impaired FOXP3 induction and inappropriate adaptive T regulatory cell differentiation results in vitro and in vivo. The epigenetic transmittance of adaptive T regulatory cell deficiency is demonstrated throughout more than 40 generations of mice. These results provide insight into chromatin remodeling events key to phenotypic features of distinct T cell populations.