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1、Regulation of inflammatory gene expressionZhu-Zhong MeiDepartment of PathophysiologyA short introduction of inflammationFirst defined by Roman doctor Cornelius Celsus in the 1st century AD. cardinal signs of inflammation: rubor et tumor cum calore et dolore (redness, swelling, heat and pain)In 1858,
2、 German doctor Rudolph Virchow added the fifth cardinal sign: functio laesa (disturbance of function). Inflammation: a complex response initiated by the innate immune systemPathogenic invasion PAMP: pathogen associated molecular pattern (LPS, BLP, flagellin, lipoproteins, zymosan, RNA )Sterile infla
3、mmation DAMP: damage associated molecular pattern (HMGB1, S100 proteins, ATP, Uric acid, histon)Pattern recognition receptor (PRR) TLRs (Toll-like receptors), NLRs (NOD-like receptors), RLRs (RIG-I-like receptors), CLRs (C-type lectin receptors), RAGECoordinated responsesConsequences of dysregulated
4、 inflammationAcute inflammation: septic shock, multiple organ dysfunction and death; Chronic inflammation: autoimmunity, atherosclerosis, diabetes, cancer, neurodegeration Regulation of eukaryotic gene expressionEpigenetic regulationEpigenetics - On or over the genetic information encoded in the DNA
5、. Gene-regulatory information that is not expressed in DNA sequences is transmitted from one generation (of cells or organisms) to the next generation. Stable changes in gene expression caused by changes in chromatin structure.DNA methylation and inflammationDNA methylation and inflammationCovalent
6、transfer of a methyl group from S-adenosyl-L-methionine to cytosines in CpG dinucleotides.Catalyzed by DNA methyltransferase, such as DNMT1, DNMT3a and DNMT3b. DNA methylation is associated with the expression of TLR2 and TLR4. Enviroment factors including bacterial infection were shown to contribut
7、e to the epigenetic status of the genome. Histone modificationsHistone modifying enzymes generate “the histone code”; PTMs dictate chromatin structure and serve as a scaffold for additional regulatory proteins; Acetylation, methylation, phosphorylation, sumolyation and ubiquitinationH3KAc, H4KAc, H3
8、K4me, H3K36me, H3K27me, H3K9meNucleosomeChromatinHistone modificationsH3K4me, H3K36me, H3K27me, H3K9me Polycomb repressive complex 1 (PRC1) and PRC2Jmjd3: an inducible enzyme that erases histone methylation, induced by exposure to bacterial products and inflammatory cytokines Histone methylation and
9、 inflammation HAT -histone acetylation (hyperacetylation) transcriptional activity HDAC -histone acetylation (hypoacetylation)transcriptional activityThe acetylation of histones results from the balance between histone acetyltransferases (HAT) and histone deacetylases (HDAC)Histone acethylation and
10、inflammationCooperation of epigenetic regulatorsNF-B signaling pathwayNF-B signaling pathwayNF-B signaling pathwayNF-B signaling pathwayIRFs: IFN regulatory factorActivation of IRFs by cytosolic PRRsTLR-mediated IRF activation pathwaysPost-transcriptional regulation of gene expressionRNA binding pro
11、teins Hundreds of RBPs encoded by the mammalian genomeRNA binding domains: RRM (RNA recognition motif), KH (K-homology) domain, RGG (Arg-Gly-Gly) box, ZnF (zinc finger)Pre-mRNA splicing and polyadenylation, RNA modification, transport, localization, translation and turnorver. Regulation of protein t
12、ranslation initiationRegulation of mRNA degradationDynamic relationship between metazoan RNA granulesImmune mRNAs subject to post-transcriptional controlImmune mRNAs subject to post-transcriptional controlPost-transcriptional control of TNF expressionSuppression of TNF expression by IL-10IL-10?TTPDUSP1TNF gene AUUAUUU TNF mRNAp38MAPKStat3HuRmiR-187Modulators of the RNA-induced silencing complexKSRP regulates the processing of certain miRNAs Coordination between RNA binding proteins and miRNAs in regulating gene expressionLPSmiR-27bLet-7KSRPTLR4iNOSPI3KNF-BThank you for your attention!
