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Epigenetics and Cancer
Jordina Casanova Vilar Genomics
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Introduction Epigenetics
Conrad Waddington: “Heritable changes in a cellular phenotype independent of alterations in the DNA sequence” Epigenetics DNA-based processes: Transcription DNA Repair Replication DNA methylation Nucleosome remodeling Histone modification RNA-mediated targeting Nebbioso A, Tambaro FP, Dell'AversanaC, Altucci L (2018) Cancer epigenetics: Moving forward. PLoS Genet 14(6): e
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Introduction Development of global proteomic and genomic technologies
Appreciation of epigenetic complexity and plasticity NGS Maps of nucleosome positioning ChIP-Seq Chromatin conformation TF binding sites Localization of histone and DNA modifications Catalog of recurrent somatic mutations in epigenetic regulators Whole-genome sequencing Identification of driver mutations implicated in oncogenesis
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Epigenetic Pathways Connected to Cancer
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1. DNA Methylation CpG islands 70% of mammalian promoters
Hypermetilation of CpG islands of tumor-supressor genes Associated with reduced expression Important in transcriptional regulation 5-10% CpG islands become abnormally methylated in cancer genomes Altered during malignant transformation Nebbioso A, Tambaro FP, Dell'AversanaC, Altucci L (2018) Cancer epigenetics: Moving forward. PLoS Genet 14(6): e
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Maintenance methyltransferase De novo methyltransferases
1. DNA Methylation DNMT3A Maintenance methyltransferase DNMT1 De novo methyltransferases DNMT3B Replication Embryogenesis Sequencing of cancer genomes: Recurrent mutations in DNMT3A in up to 25% of patients with acute myeloid leukemia (AML). Impact in prognosis. Ley, T.J., Ding, L., Walter, M.J., McLellan, M.D., Lamprecht, T., Larson, D.E., Kandoth, C., Payton, J.E., Baty, J., Welch, J., et al. (2010). DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 363, 2424–2433.
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1. DNA Methylation TET proteins
Convert 5mC to 5hmC in an Fe(II) and α-ketoglutarate-dependent manner Mutations in IDH1 and IDH2 70% of patients with secondary glioblastoma mutiforme and myeloid malignancies, most notably AML. Reduction of α-KG to 2-hydroxyglutarate Loss of function of TET2 Increase in DNA methylation levels Cimmino, L., Abdel-Wahab, O., Levine, R. and Aifantis, I. (2011). TET Family Proteins and Their Role in Stem Cell Differentiation and Transformation. Cell Stem Cell, 9(3), pp
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2. Histone Modifications KATs: Lysine Acetyltransferases
Histone Acetylation Histone Deacetylation HDACs Neutralizes lysine’s + charge weaken electrostatic interaction between histones and DNA Chimeric fusion proteins seen in leukemia recruit HDACs gene silencing “Open” chromatin conformation Relaxed structure Greater levels of gene transcription Mutation of HDAC2 in sporadic tumors with microsatellite instability and tumors in non-polyposis colorectal carcinoma HDAC2 involved in gene repression mediated by Rb Loss of function hyperacetilation reexpression of genes regulated by Rb KATs: Lysine Acetyltransferases Implicated in neoplasic transformation Viral oncoproteins associate with them Chromosomal translocations (MLL-CBP, MOZ-TIF2) Coding mutations (solid and hematological malignances) Ropero, S. and Esteller, M. (2007). The role of histone deacetylases (HDACs) in human cancer. Molecular Oncology, 1(1), pp
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2. Histone Modifications
Histone Methylation Arginine Lysine Histidine Cancer genomes: Translocations/mutations in KMT (MMSET, EZH2, MLL) PRC2 - Methylation of histone H3 (chromatin compactor) EZH2 as catalytic component Margueron, R. and Reinberg, D. (2011). The Polycomb complex PRC2 and its mark in life. Nature, 469(7330), pp Overexpression of EZH2 poor prognosis in prostate and breast cancer Coding mutations in EZH2 in lymphoid and myeloid neoplasms
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2. Histone Modifications
Histone Phosphorylation Mitosis, apoptosis, DNA repair, replication, transcription Serine Threonine Tyrosine Frequently amplified/mutated in hematological malignancies TK JAK2 Activates expression of hematopoietic oncogenes (Lm2o, MYC) Phosphorylates H3Y41 disrupts chromatin repressor HP1a binding Dawson, M.A., Bannister, A.J., Go¨ ttgens, B., Foster, S.D., Bartke, T., Green, A.R., and Kouzarides, T. (2009). JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin. Nature 461, 819–822.
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3. Non-coding RNAs Increasingly recognized to be vital for normal development and compromised in diseases such as cancer lncRNAs critical function at chromatin: chaperones or scaffolds for chromatin regulators HOTAIR Manipulation of HOTAIR levels within malignant cells can alter the invasive potential Molecular scaffold for PRC2 complex (chromatin compactor) Aberrantly overexpressed in advanced breast and colorectal cancer Kogo, R., et al. (2011). Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res. 71,6320–6326. Wang, K.C., and Chang, H.Y. (2011). Molecular mechanisms of long noncoding RNAs. Mol. Cell 43, 904–914.
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Epigenetic pathways missregulation can culminate in cancer
Conclusions DNA methylation, histone modification, and RNA-mediated targeting regulate many biological processes that are relevant for the genesis of cancer Epigenetic pathways missregulation can culminate in cancer Appreciation of epigenetic complexity and plasticity has increased over the last few years following the development of several global proteomic and genomic technologies Identification of driver mutations provide potential targets for therapeutic intervention
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Bibliography Cimmino, L., Abdel-Wahab, O., Levine, R. and Aifantis, I. (2011). TET Family Proteins and Their Role in Stem Cell Differentiation and Transformation. Cell Stem Cell, 9(3), pp Dawson, M. and Kouzarides, T. (2012). Cancer Epigenetics: From Mechanism to Therapy. Cell, 150(1), pp Dawson, M.A., Bannister, A.J., Go¨ ttgens, B., Foster, S.D., Bartke, T., Green, A.R., and Kouzarides, T. (2009). JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin. Nature 461, 819–822. Kogo, R., et al. (2011). Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res. 71,6320–6326 Ley, T.J., Ding, L., Walter, M.J., McLellan, M.D., Lamprecht, T., Larson, D.E., Kandoth, C., Payton, J.E., Baty, J., Welch, J., et al. (2010). DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 363, 2424–2433. Margueron, R. and Reinberg, D. (2011). The Polycomb complex PRC2 and its mark in life. Nature, 469(7330), pp Nebbioso A, Tambaro FP, Dell'AversanaC, Altucci L (2018) Cancer epigenetics: Moving forward. PLoS Genet 14(6): e Ropero, S. and Esteller, M. (2007). The role of histone deacetylases (HDACs) in human cancer. Molecular Oncology, 1(1), pp Wang, K.C., and Chang, H.Y. (2011). Molecular mechanisms of long noncoding RNAs. Mol. Cell 43, 904–914.
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