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Unravelling the Role of the Histone Demethylase Jarid1b in Macrophages

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Unravelling the Role of the Histone Demethylase Jarid1b in Macrophages PhD degree in Molecular Medicine European School of Molecular Medicine (SEMM) University of Milan and University of Naples “Federico II” Faculty of Medicine Settore disciplinare: MED/04 UNRAVELLING THE ROLE OF THE HISTONE DEMETHYLASE JARID1B IN MACROPHAGES Samuele Notarbartolo IFOM-IEO Campus, Milan Matricola n. R07389 Supervisor: Dr. Gioacchino Natoli IFOM-IEO Campus, Milan Added co-Supervisor: Dr. Giuseppe Testa IFOM-IEO Campus, Milan Anno accademico 2009-2010 INDEX INDEX ...................................................................................................................................2 LIST OF ABBREVIATIONS................................................................................................4 FIGURE INDEX....................................................................................................................7 TABLE INDEX ...................................................................................................................10 ABSTRACT.........................................................................................................................11 INTRODUCTION ...............................................................................................................13 1. Inflammation............................................................................................................13 1.1 A complex transcriptional response underlies inflammation...................................15 1.2 Inflammation is a tightly regulated process .............................................................16 1.3 Resolution of inflammation .....................................................................................18 2. Inflammation and metabolism .................................................................................20 2.1 Integration of inflammation and lipid metabolism in macrophages: the nuclear receptor pathways.............................................................................................................22 3. Modelling transcriptional networks: the feed-forward loop ....................................27 4. Chromatin organization and modifications..............................................................28 4.1 Methylation of lysine 4 on histone 3........................................................................29 4.2 H3K4 methylation is a dynamic chromatin mark ....................................................33 4.3 The JARID1 family..................................................................................................37 4.4 Jarid1b/Kdm5b.........................................................................................................41 5. Thesis outline ...........................................................................................................44 MATERIALS AND METHODS.........................................................................................46 RESULTS ............................................................................................................................57 1. Jarid1b expression is up-regulated in LPS stimulated macrophages .......................58 2. Jarid1b up-regulation is under the control of Hif1α ................................................62 3. Jarid1b depletion impairs LXR target genes expression..........................................68 2 4. Jarid1b depletion impairs LXR activation ...............................................................72 5. Generation of Jarid1b knock-out mice.....................................................................80 6. Characterization of Jarid1b knock-out macrophages transcriptome........................83 7. Characterization of Jarid1b enzymatic activity and genomic binding.....................96 SUPPLEMENTARY TABLE............................................................................................101 DISCUSSION ....................................................................................................................105 BIBLIOGRAPHY..............................................................................................................113 ACKNOWLEDGMENTS .................................................................................................121 3 LIST OF ABBREVIATIONS 2OG 2-oxoglutarate 5'-TOP 5'-terminal oligopyrimidine α-KG alpha-ketoglutarate Ala alanine AP-1 activator protein 1 ARID A/T rich interactive domain BM Bone marrow BMDM Bone marrow-derived macrophages bp base pair BSA Bovine serum albumin Ccl chemokine (C-C motif) ligand cDNA complementary DNA ChIP chromatin immunoprecipitation ChIP-seq ChIP-sequencing CREB1 cAMP-responsive-element-binding protein 1 CsA cyclosporin A CTD carboxy-terminal domain C-terminal carboxy-terminal Ctrl control Cxcl chemokine (C-X-C motif) ligand Cys cysteine ddH2O double-distilled water dNTP deoxynucleotide tri-phosphate ES cell embryonic stem cell FBS Fetal bovine serum F.C. Fold change FDR False discovery rate FFL feed forward loop GO Gene Ontology H2AK119 lysine 119 on histone 2A H3 histone 3 H3K4 lysine 4 on histone 3 H3K9 lysine 9 on histone 3 H3K27 lysine 27 in histone 3 H3K36 lysine 36 on histone 3 H3K79 lysine 79 on histone 3 H3S10 serine 10 on histone 3 H4K20 lysine 20 on histone 4 4 HA hemagglutinin HDAC histone deacetylase Het heterozygous Hif1α hypoxia inducible factor 1, alpha subunit HMT histone methyltransferase HSC hematopoietic stem cell IFNγ interferon gamma IκBα NF-κB inhibitor alpha IKK inhibitor of kappaB kinase Il interleukin IP immunoprecipitation IRF IFN-regulatory factors Jmj Jumonji kb kilobase KD knock-down KDM lysine-specific demethylase KO knock-out LPS lipopolysaccharide Luc (firefly) luciferase LXR Liver X Receptor LXRE LXR responsive element MBP maltose binding protein -me1 monomethylated lysine residue -me2 dimethylated lysine residue -me3 trimethylated lysine residue MEF mouse embryonic fibroblast MEKK1 MAPK/ERK kinase kinase 1 M-MuLV Moloney Murine Leukemia Virus mRNA messenger RNA NFAT nuclear factor of activated T-cells NF-κB nuclear factor of kappa light polypeptide gene enhancer in B-cells N-teminal amino-terminal o.n. over night QPCR quantitative PCR PBS phosphate buffered saline PCR Polymerase chain reaction PHD plant homeodomain Phe phenylalanine PWM Position-specific weight matrix PolII polymerase II PPAR peroxisome proliferator-activated receptor PRC2 Polycomb repressive complex 2 RNAi RNA interference 5 rpm revolutions per minute rRNA ribosomal RNA RT room temperature RXR retinoid X receptor SAM S-adenosyl-methionine SDS Sodium Dodecyl Sulphate Ser serine shRNA short hairpin RNA siRNA short interfering RNA snoRNA small nucleolar RNA STAT signal transducer and activator of transcription Surn supernatant TBP TATA binding protein TF transcription factor TLR4 toll-like receptor 4 Trp tryptophan TSS transcription start site Tyr tyrosine UTR Untranslated Region VDR vitamin D receptor WB Western blot WCE whole-cell extract WT wild-type XLMR X-linked mental retardation 6 FIGURE INDEX Figure 1 - Activation of the classical NF-κB pathway by TLR4.........................................14 Figure 2 - Evolution of adipose tissue, the liver and the haematopoietic system into distinct organs in mammals. .............................................................................................................21 Figure 3 - Nuclear receptor “derepression”. ........................................................................23 Figure 4 - Morphology of livers from LXRα KO vs. WT mice on high-cholesterol diet. ..25 Figure 5 - Integration of lipid metabolic and inflammatory signalling in macrophages by LXRs. ...................................................................................................................................26 Figure 6 – Feed-forward loops (FFLs).................................................................................27 Figure 7 - Two examples of characterized feed-forward loop (FFL) involved in the inflammatory response.........................................................................................................28 Figure 8 - Schematic representation of the interactions between MLL complex components. .........................................................................................................................31 Figure 9 - Mechanisms of H3K4 methyltransferases recruitment to target genes...............32 Figure 10 - Phylogenetic analysis of the human JmjC family. ............................................35 Figure 11 – JmjC containing proteins catalyze oxidative reactions.....................................36 Figure 12 – JmjC-driven demethylation reaction on a methylated lysine residue...............37 Figure 13 - Schematic representation of Jarid1b domains...................................................42 Figure 14 - Gene trap strategy..............................................................................................56 Figure 15 - Putative transcriptional co-regulators involved in the inflammatory response.57 Figure 16 - Jarid1b expression is up-regulated in bone marrow-derived macrophages and macrophage cell lines upon inflammatory stimuli...............................................................59 Figure 17 - LPS is sufficient to induce Jarid1b up-regulation. ...........................................60 Figure 18 - JARID1 family members are not induced in response to inflammatory stimuli. ................................................................................................................... 61_Toc273550496
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