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1、Regulation of inflammatory gene expression,Zhu-Zhong Mei Department of Pathophysiology,A short introduction of inflammation,First 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
2、1858, German doctor Rudolph Virchow added the fifth cardinal sign: functio laesa (disturbance of function).,Inflammation: a complex response initiated by the innate immune system,Pathogenic invasion PAMP: pathogen associated molecular pattern (LPS, BLP, flagellin, lipoproteins, zymosan, RNA ) Steril
3、e inflammation 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), RAGE Coordinated responses,Consequences of dy
4、sregulated inflammation,Acute inflammation: septic shock, multiple organ dysfunction and death; Chronic inflammation: autoimmunity, atherosclerosis, diabetes, cancer, neurodegeration ,Regulation of eukaryotic gene expression,Epigenetic regulation,Epigenetics - On or over the genetic information enco
5、ded in the DNA. 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 inflammation,DNA methylation and infla
6、mmation,Covalent 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
7、shown to contribute to the epigenetic status of the genome.,Histone modifications,Histone modifying enzymes generate “the histone code”; PTMs dictate chromatin structure and serve as a scaffold for additional regulatory proteins; Acetylation, methylation, phosphorylation, sumolyation and ubiquitinat
8、ion H3KAc, H4KAc, H3K4me, H3K36me, H3K27me, H3K9me,Histone modifications,H3K4me, H3K36me, H3K27me, H3K9me Polycomb repressive complex 1 (PRC1) and PRC2 Jmjd3: an inducible enzyme that erases histone methylation, induced by exposure to bacterial products and inflammatory cytokines,Histone methylation
9、 and inflammation,HAT -histone acetylation (hyperacetylation) transcriptional activity HDAC -histone acetylation (hypoacetylation) transcriptional activity,The acetylation of histones results from the balance between histone acetyltransferases (HAT) and histone deacetylases (HDAC),Histone acethylati
10、on and inflammation,Cooperation of epigenetic regulators,NF-B signaling pathway,NF-B signaling pathway,NF-B signaling pathway,NF-B signaling pathway,IRFs: IFN regulatory factor,Activation of IRFs by cytosolic PRRs,TLR-mediated IRF activation pathways,Post-transcriptional regulation of gene expressio
11、n,RNA binding proteins,Hundreds of RBPs encoded by the mammalian genome RNA 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.,Regu
12、lation of protein translation initiation,Regulation of mRNA degradation,Dynamic relationship between metazoan RNA granules,Immune mRNAs subject to post-transcriptional control,Immune mRNAs subject to post-transcriptional control,Post-transcriptional control of TNF expression,Suppression of TNF expression by IL-10,DUSP1,miR-187,Modulators of the RNA-induced silencing complex,KSRP regulates the processing of certain miRNAs,Coordination between RNA binding proteins and miRNAs in regulating gene expression,LPS,miR-27b,Let-7,KSRP,TLR4,iNOS,PI3K,NF-B,Thank you for your attention!,