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nullEpigenetics and DiseasesEpigenetics and DiseasesJan-Gowth Chang, MD., Professor Center of RNA Biology and Clinical Application China Medical University and Hospital 101.11.12nullnull院史沿革中國醫藥學院成立 (覃勤、陳固、陳恭炎創辦) (覃勤先生擔任第一任董事長)民國47年王廷輔醫師擔任創院院長 醫院開幕69年蔡長海教授接任第二任院長84年晉升醫學中心89年林正介教授接任第三任院長 蔡長海教授接任第六任董事長90年晉升準醫學中心86年區域教學醫院77年(220床)(1,033床)(1,290床)(1,723床)(779床)93年再度通過醫學中心評鑑96年癌症中心大樓及急重症中心大樓啟用(2,062床)97年與安德森癌症中心締結姊妹機構通過新制教學醫院及醫學中心評鑑周德陽教授接任第四任院長98年97年通過JCI評鑑98年99年通過衛生署『緊急醫療能力』為最佳重度等級Phenotypes of spinal muscular atrophyPhenotypes of spinal muscular atrophyCurr Opin Neurol 23:450–458Phenotypes of SMA-like micePhenotypes of SMA-like miceNat Genet. 2000 Jan;24(1):66-70.Treatment of SMA mouseTreatment of SMA mouseUntreated Normal TreatedPNAS / August 14, 2001 / vol. 98 / no. 175-(N-ethyl-N-isopropyl)-amiloride (EIPA) promotes survival motor neuron 2 (SMN2) exon 7 inclusion5-(N-ethyl-N-isopropyl)-amiloride (EIPA) promotes survival motor neuron 2 (SMN2) exon 7 inclusionAnn Neurol 2008;63:26–34nullnullHypothetical schematic diagram of the amiloride-induced alternative splicing in K562 cellsChang W et al. Cancer Res 2011;71:383-392Genome organizationGenome organizationBiochimica et Biophysica Acta 1819 (2012) 401–410Comprehensive model for the highly conserved role of insulators in nuclear organizationComprehensive model for the highly conserved role of insulators in nuclear organizationAnnu. Rev. Cell Dev. Biol.(2012) 28:18.1-18.25The well studied epigenetic mechanisms are DNA methylation and histone modificationThe well studied epigenetic mechanisms are DNA methylation and histone modificationJ Med Genet (2011) 48:721-730Transcriptional regulation at the epigenetic levelTranscriptional regulation at the epigenetic levelInternational Journal of Epidemiology (2012) 41:79-105Potential pathways for DNA demethylationPotential pathways for DNA demethylationGenetics (2012) 13:7-13DNA methylation status affects gene transcriptionDNA methylation status affects gene transcriptionNeuron. (2011) 70(5):813-829Epigenetic modifications-histoneEpigenetic modifications-histoneBiologics: Target and Therapy (2012) 6:307-327Schematic representation of epigenetic modificationsSchematic representation of epigenetic modificationsJ Mol Med (2012) 90:791-801Dynamic regulation and diverse effects of histone lysine methylation on gene transcriptionDynamic regulation and diverse effects of histone lysine methylation on gene transcriptionHormones and Behavior (2011) 59:383-392Diagram of interactions that regulate DNA methylation and association histone H3 modificationsDiagram of interactions that regulate DNA methylation and association histone H3 modificationsBiochemistry (2010) 49:2999-3008ncRNA molecules can serve as top-level regulators in networksncRNA molecules can serve as top-level regulators in networksBiochimica et Biophysica Acta 1799 (2010) 597–615Small antisense RNA-directed transcriptional gene silencingSmall antisense RNA-directed transcriptional gene silencingClin Epigenetics. (2011) 2(2): 433–437Endogenous antisense non-coding RNA mediated transcriptional silencing and activationEndogenous antisense non-coding RNA mediated transcriptional silencing and activationClin Epigenetics. (2011) 2(2): 433–437LncRNA-protein network in gene transcription program regulation LncRNA-protein network in gene transcription program regulation Cold Spring Harb Perspect Biol. 2011 Jan 1;3(1):a003756 The crosstalk between disease genetics and epigenetics The crosstalk between disease genetics and epigenetics Cancer Cell (2012) 22:9-20Common methylated genes identified at the histologic steps of the colorectal cancer polyp-adenoma-carcinoma sequenceCommon methylated genes identified at the histologic steps of the colorectal cancer polyp-adenoma-carcinoma sequenceNat Rev Gastroenterol Hepatol (2012) 8(12):686-700Monogenetic brain disorders associated with DNA methylation and hostone-modification defectsMonogenetic brain disorders associated with DNA methylation and hostone-modification defectsNature Medicine (2012) 18(8):1195-1205Monogenetic brain disorders with a heterochromatin defectMonogenetic brain disorders with a heterochromatin defectNature Medicine (2012) 18(8):1195-1205Cancer mutations affecting epigenetic regulators of DNA methylationCancer mutations affecting epigenetic regulators of DNA methylationCell (2012) 150:9-20Cancer mutations affecting epigenetic regulators of histone acetylationCancer mutations affecting epigenetic regulators of histone acetylationCell (2012) 150:9-20Cancer mutations affecting epigenetic regulators of histone methylationCancer mutations affecting epigenetic regulators of histone methylationCell (2012) 150:9-20Cancer mutations affecting epigenetic regulators of histone phosphorylationCancer mutations affecting epigenetic regulators of histone phosphorylationCell (2012) 150:9-20Classic epigenetic mechanisms related to the pathogenesis of strokeClassic epigenetic mechanisms related to the pathogenesis of strokeArch Neurol (2010) 67(11):1316-1322Epigenetic regulatory mechanisms in strokeEpigenetic regulatory mechanisms in strokeArch Neurol (2010) 67(11):1316-1322Summary of epigenetic mechanisms involved in autoimmune diseasesSummary of epigenetic mechanisms involved in autoimmune diseasesAutoimmune Diseases (2012) 593720:1-16Epigenetic modulation of tumor-initiating cells and therapy resistanceEpigenetic modulation of tumor-initiating cells and therapy resistanceNature Medicine (2011) 17(3):288-289Genetic and epigenetic modifiers in diseaseGenetic and epigenetic modifiers in diseaseCancer Cell (2012) 22:12-27DISEASE The percentage of protein-coding genes sequences in several eukaryotic and bacterial genomesThe percentage of protein-coding genes sequences in several eukaryotic and bacterial genomesJournal of Translational Medicine (2012) 10(103):1-21The human genomeThe human genomeHum Mutat. 2010 Jun;31(6):631-55 Production of RNAsProduction of RNAsTrends Mol Med. 2011 Jun;17(6):337-346 Types of recently discovered human non-coding RNAsTypes of recently discovered human non-coding RNAsJournal of Translational Medicine (2012) 10(103):1-21The biogenesis, mode of action of miRNAs, and various research tools useful in miRNA researchThe biogenesis, mode of action of miRNAs, and various research tools useful in miRNA researchCardiovascular Reasearch (2012) 93:545-554Novel published miRNA targets in cardiovascular pathophysiologyNovel published miRNA targets in cardiovascular pathophysiologyCardiovascular Reasearch (2012) 93:545-554miRNAs in human body fluids are non-invasive diagnostic markers for cancersmiRNAs in human body fluids are non-invasive diagnostic markers for cancersCancer Sci. (2010) 101(10):2087-2092Research on long non-coding RNAs is rapidly increasing Research on long non-coding RNAs is rapidly increasing Semin Cell Dev Biol. 2011 Dec 20. Schematic illustration of IncRNAs functioningSchematic illustration of IncRNAs functioningJournal of Translational Medicine (2012) 10(103):1-21Schematic diagram of the four mechanisms of IncRNAs functioningSchematic diagram of the four mechanisms of IncRNAs functioningJournal of Translational Medicine (2012) 10(103):1-21Human cancer associated IncRNAs Human cancer associated IncRNAs Journal of Translational Medicine (2012) 10(103):1-21Very large ncRNA*Very large ncRNALength：＞5Kb Rarely studied for the role of very large ncRNA in the development of cancers At present majority of studies are done for XIST and MALAT-1..ect The expression patterns and clinical significance of 40 vlncRNAs in 62 HCC patientsThe expression patterns and clinical significance of 40 vlncRNAs in 62 HCC patientsNTT transcriptNTT transcriptNon-coding Transcript in T cells (Liu et al., 1997) In 1997, Liu et al. first discovery this gene 17,548 base, non-spliced, single-copy gene With poly-A tail and L1, Alu, and MER 38 repeat regions Chromosome 6q23- q24 NTT gene proximity to the interferon-g receptor 1 gene (IFN-gR1; 6q23.3) and shared expression pattern suggest a possible function relationship between the two. (Liu et al., 1997) NTT can be up-regulation by PHA and PMA + ionmycin in T cells. RNA-FISH result of NTT transcripts in HCC specimen RNA-FISH result of NTT transcripts in HCC specimen Knockdown of NTT (siNTT) enhanced cell proliferation and migration in both HCC (HepG2) and non-HCC (GBM8401) cellsKnockdown of NTT (siNTT) enhanced cell proliferation and migration in both HCC (HepG2) and non-HCC (GBM8401) cellsNTT’s transcripts coated around the 6q23 region of chromosome 6 in HepG2 cells and down-regulation of 3 genesNTT’s transcripts coated around the 6q23 region of chromosome 6 in HepG2 cells and down-regulation of 3 genesNTT transcripts co-localized with proteins of PRC2 complex in HepG2 cellsNTT transcripts co-localized with proteins of PRC2 complex in HepG2 cellsNTT transcripts colocalized with with mRNAs of BCLAF1, TNFAIP3/A20, and INFgR1 in HepG2 cells NTT transcripts colocalized with with mRNAs of BCLAF1, TNFAIP3/A20, and INFgR1 in HepG2 cells RNA-IP results showed that these RNAs of NTT, BCLAF1, TNFAIP3/A20, and INFgR1 bound directly to the protein components of PRC2, DNMT3a, G9a, and H3K9me3 NTT down-regulation in 62 patients with HCC was correlated with the increase in mRNA levels of BCLAF1, INFgR1, and TNFAIP3/A20 in tumor tissueshigh6q22-236q23.36q23N=62 NTT down-regulation in 62 patients with HCC was correlated with the increase in mRNA levels of BCLAF1, INFgR1, and TNFAIP3/A20 in tumor tissuessiNTT enhanced the expression of 3 neighboring genes, and reduced its colocalization with EED in HepG2 cells siNTT enhanced the expression of 3 neighboring genes, and reduced its colocalization with EED in HepG2 cells NTT colocalized with DNMT3a, G9a, and H3K9me3 but not H3K27me3 in HCC cellsNTT colocalized with DNMT3a, G9a, and H3K9me3 but not H3K27me3 in HCC cellsThe proposed model of NTT in the silencing of neighboring protein-coding genes The proposed model of NTT in the silencing of neighboring protein-coding genes nullPseudogeneTranscribed Pseudogene (TPG)TranscriptionNon-coding RNAIsPseudogene-mediated production of endo-siRNAs in mouse and DrosophilaPseudogene-mediated production of endo-siRNAs in mouse and DrosophilaNature 453: 729-731, 2008.HypothesisHypothesisIdentification of TPG-derived esiRNAsIdentification of TPG-derived esiRNAsSchematic representation of ΨPPM1K and its parental geneSchematic representation of ΨPPM1K and its parental geneCandidate PPM1K-derived esiRNAs and their targetsCandidate PPM1K-derived esiRNAs and their targetsExpression patterns of HCC tissues and cell linesExpression patterns of HCC tissues and cell linesEffect of overexpressed PPM1K on cell growth and clonogenic activity in transfected Huh-7 cell clonesEffect of overexpressed PPM1K on cell growth and clonogenic activity in transfected Huh-7 cell clonesPrediction of esiRNA-targetsPrediction of esiRNA-targetsΨPPM1K-derived esiRNA1 target predictionΨPPM1K-derived esiRNA1 target predictionExpression of predicted target Genes in HCC cell clones transfected with PPM1KExpression of predicted target Genes in HCC cell clones transfected with PPM1KExpression of PPM1K-dervied esiRNAsExpression of PPM1K-dervied esiRNAsExpression of NEK8 in Huh-7 Cells Transfected with Synthetic siRNA1Expression of NEK8 in Huh-7 Cells Transfected with Synthetic siRNA1ΨPPM1K alters PPM1K expression and mitochondrial functionΨPPM1K alters PPM1K expression and mitochondrial functionTPG acts as a miRNA decoyTPG acts as a miRNA decoyNature 465: 1033-1038, 2010.miRNA regulation of PPM1K and ΨPPM1KmiRNA regulation of PPM1K and ΨPPM1KPossible genetic regulatory mechanisms involving ΨPPM1KPossible genetic regulatory mechanisms involving ΨPPM1K誌謝誌謝高醫大 血液腫瘤科 劉大智 教授 高醫大 生物科技學系 邱建智 助理教授 高醫大 生物醫學暨環境生物學系 游仲逸 副教授 北醫大 林時宜 教授 中醫大 臨床醫學系 楊文光 教授 交通大學生物資訊及系統生物所 黃憲達 教授 博士後研究員 洪詩雅 張雅璇 李建志 博士班學生 張由俐 詹雯玲 Genetic and epigenetic changes in diseasesGenetic and epigenetic changes in diseasesModified from Cancer Cell (2012) 22:12-27NON-CODING RNAmiRNA siRNA piRNA lncRNA pseudogeneHistone modification inhibitors and their targetsHistone modification inhibitors and their targetsBiochimica et Biophysica (2010) 1799:810-828DNA methylation-mediated abrrant gene silencing in cancerDNA methylation-mediated abrrant gene silencing in cancerCell Research (2011) 21:502-517Summary of factors that may lead to development of autoimmunitySummary of factors that may lead to development of autoimmunityBiologics: Target and Therapy (2012) 6:307-327Epigenetic changes and cancer developmentEpigenetic changes and cancer developmentLandscape of genomics and epigenomics analysis of diseasesLandscape of genomics and epigenomics analysis of diseasesModified from Human Molecular Genetics (2010) 19(R2):R188-R196& other epigenetic changesThe possible factors for gout developmentThe possible factors for gout development“Gout”GoutGoutGoutThe future of gout studyThe future of gout studyModified from Cancer Cell (2012) 22:12-27NON-CODING RNAmiRNA siRNA piRNA lncRNA pseudogeneGout Thanks for your attentions!Thanks for your attentions!Epigenetic alterations during oncogenesis Epigenetic alterations during oncogenesis Cell. Mol. Life Sci. (2011) 68:1681-1702Changes in epigenetic marks seen in the target tissue of some autoimmune diseasesChanges in epigenetic marks seen in the target tissue of some autoimmune diseasesBiologics: Target and Therapy (2012) 6:307-327Genome-wide mapping of histone modifications on the DNAs Genome-wide mapping of histone modifications on the DNAs J Med Genet (2011) 48:721-730Abnormal epigenetic marks on peripheral blood leukocytes in autoimmune diseasesAbnormal epigenetic marks on peripheral blood leukocytes in autoimmune diseasesBiologics: Target and Therapy (2012) 6:307-327Common approaches to mapping DNA methylation and histone modificationsCommon approaches to mapping DNA methylation and histone modificationsJ Med Genet (2011) 48:721-730