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  • 1
    Publication Date: 2012-02-22
    Description: Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 have been identified in gliomas, acute myeloid leukaemias (AML) and chondrosarcomas, and share a novel enzymatic property of producing 2-hydroxyglutarate (2HG) from alpha-ketoglutarate. Here we report that 2HG-producing IDH mutants can prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells. In tumour samples from glioma patients, IDH mutations were associated with a distinct gene expression profile enriched for genes expressed in neural progenitor cells, and this was associated with increased histone methylation. To test whether the ability of IDH mutants to promote histone methylation contributes to a block in cell differentiation in non-transformed cells, we tested the effect of neomorphic IDH mutants on adipocyte differentiation in vitro. Introduction of either mutant IDH or cell-permeable 2HG was associated with repression of the inducible expression of lineage-specific differentiation genes and a block to differentiation. This correlated with a significant increase in repressive histone methylation marks without observable changes in promoter DNA methylation. Gliomas were found to have elevated levels of similar histone repressive marks. Stable transfection of a 2HG-producing mutant IDH into immortalized astrocytes resulted in progressive accumulation of histone methylation. Of the marks examined, increased H3K9 methylation reproducibly preceded a rise in DNA methylation as cells were passaged in culture. Furthermore, we found that the 2HG-inhibitable H3K9 demethylase KDM4C was induced during adipocyte differentiation, and that RNA-interference suppression of KDM4C was sufficient to block differentiation. Together these data demonstrate that 2HG can inhibit histone demethylation and that inhibition of histone demethylation can be sufficient to block the differentiation of non-transformed cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478770/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478770/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lu, Chao -- Ward, Patrick S -- Kapoor, Gurpreet S -- Rohle, Dan -- Turcan, Sevin -- Abdel-Wahab, Omar -- Edwards, Christopher R -- Khanin, Raya -- Figueroa, Maria E -- Melnick, Ari -- Wellen, Kathryn E -- O'Rourke, Donald M -- Berger, Shelley L -- Chan, Timothy A -- Levine, Ross L -- Mellinghoff, Ingo K -- Thompson, Craig B -- R01 CA078831/CA/NCI NIH HHS/ -- R01 CA105463/CA/NCI NIH HHS/ -- U54CA143798/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Feb 15;483(7390):474-8. doi: 10.1038/nature10860.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22343901" target="_blank"〉PubMed〈/a〉
    Keywords: 3T3-L1 Cells ; Adipocytes/cytology/drug effects/metabolism ; Animals ; Astrocytes/cytology/drug effects ; Cell Differentiation/drug effects/*genetics ; Cell Line, Tumor ; Cell Lineage/genetics ; DNA Methylation/drug effects ; Enzyme Induction/drug effects ; Gene Expression Regulation/drug effects ; Glioma/enzymology/genetics/pathology ; Glutarates/metabolism/pharmacology ; HEK293 Cells ; Histones/*metabolism ; Humans ; Isocitrate Dehydrogenase/antagonists & inhibitors/*genetics/metabolism ; Jumonji Domain-Containing Histone Demethylases/antagonists & ; inhibitors/deficiency/genetics/metabolism ; Methylation/drug effects ; Mice ; Mutation/*genetics ; Neural Stem Cells/metabolism ; Promoter Regions, Genetic/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2015-11-03
    Description: Macroautophagy (hereafter referred to as autophagy) is a catabolic membrane trafficking process that degrades a variety of cellular constituents and is associated with human diseases. Although extensive studies have focused on autophagic turnover of cytoplasmic materials, little is known about the role of autophagy in degrading nuclear components. Here we report that the autophagy machinery mediates degradation of nuclear lamina components in mammals. The autophagy protein LC3/Atg8, which is involved in autophagy membrane trafficking and substrate delivery, is present in the nucleus and directly interacts with the nuclear lamina protein lamin B1, and binds to lamin-associated domains on chromatin. This LC3-lamin B1 interaction does not downregulate lamin B1 during starvation, but mediates its degradation upon oncogenic insults, such as by activated RAS. Lamin B1 degradation is achieved by nucleus-to-cytoplasm transport that delivers lamin B1 to the lysosome. Inhibiting autophagy or the LC3-lamin B1 interaction prevents activated RAS-induced lamin B1 loss and attenuates oncogene-induced senescence in primary human cells. Our study suggests that this new function of autophagy acts as a guarding mechanism protecting cells from tumorigenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dou, Zhixun -- Xu, Caiyue -- Donahue, Greg -- Shimi, Takeshi -- Pan, Ji-An -- Zhu, Jiajun -- Ivanov, Andrejs -- Capell, Brian C -- Drake, Adam M -- Shah, Parisha P -- Catanzaro, Joseph M -- Ricketts, M Daniel -- Lamark, Trond -- Adam, Stephen A -- Marmorstein, Ronen -- Zong, Wei-Xing -- Johansen, Terje -- Goldman, Robert D -- Adams, Peter D -- Berger, Shelley L -- P01AG031862/AG/NIA NIH HHS/ -- R01 CA078831/CA/NCI NIH HHS/ -- R01 GM106023/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Nov 5;527(7576):105-9. doi: 10.1038/nature15548. Epub 2015 Oct 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Epigenetics Program, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. ; Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA. ; Institute of Cancer Sciences, University of Glasgow and Beatson Institute for Cancer Research, Glasgow G61 1BD, UK. ; Department of Biochemistry &Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Molecular Cancer Research Group, Institute of Medical Biology, University of Tromso - The Arctic University of Norway, 9037 Tromso, Norway. ; Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26524528" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/metabolism ; Animals ; *Autophagy ; Cell Aging ; Cell Transformation, Neoplastic ; Cells, Cultured ; Chromatin/chemistry/metabolism ; Cytoplasm/metabolism ; Fibroblasts ; HEK293 Cells ; Humans ; Lamin Type B/genetics/metabolism ; Lysosomes/metabolism ; Mice ; Microfilament Proteins/metabolism ; Microtubule-Associated Proteins/metabolism ; Nuclear Lamina/*metabolism ; Oncogene Protein p21(ras)/metabolism ; Protein Binding ; Proteolysis
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2015-09-04
    Description: TP53 (which encodes p53 protein) is the most frequently mutated gene among all human cancers. Prevalent p53 missense mutations abrogate its tumour suppressive function and lead to a 'gain-of-function' (GOF) that promotes cancer. Here we show that p53 GOF mutants bind to and upregulate chromatin regulatory genes, including the methyltransferases MLL1 (also known as KMT2A), MLL2 (also known as KMT2D), and acetyltransferase MOZ (also known as KAT6A or MYST3), resulting in genome-wide increases of histone methylation and acetylation. Analysis of The Cancer Genome Atlas shows specific upregulation of MLL1, MLL2, and MOZ in p53 GOF patient-derived tumours, but not in wild-type p53 or p53 null tumours. Cancer cell proliferation is markedly lowered by genetic knockdown of MLL1 or by pharmacological inhibition of the MLL1 methyltransferase complex. Our study reveals a novel chromatin mechanism underlying the progression of tumours with GOF p53, and suggests new possibilities for designing combinatorial chromatin-based therapies for treating individual cancers driven by prevalent GOF p53 mutations.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568559/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568559/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhu, Jiajun -- Sammons, Morgan A -- Donahue, Greg -- Dou, Zhixun -- Vedadi, Masoud -- Getlik, Matthaus -- Barsyte-Lovejoy, Dalia -- Al-awar, Rima -- Katona, Bryson W -- Shilatifard, Ali -- Huang, Jing -- Hua, Xianxin -- Arrowsmith, Cheryl H -- Berger, Shelley L -- 092809/Z/10/Z/Wellcome Trust/United Kingdom -- P30 ES013508/ES/NIEHS NIH HHS/ -- R01 CA078831/CA/NCI NIH HHS/ -- R01 GM069905/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Sep 10;525(7568):206-11. doi: 10.1038/nature15251. Epub 2015 Sep 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Biomedical Graduate Studies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada. ; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada. ; Abramson Family Cancer Research Institute, Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 320 E. Superior Street, Chicago, Illinois 60611, USA. ; Cancer and Stem Cell Epigenetics, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA. ; Princess Margaret Cancer Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C4, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26331536" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Animals ; Cell Line, Tumor ; Cell Proliferation/genetics ; Chromatin/chemistry/*genetics/*metabolism ; Female ; Genes, Tumor Suppressor ; Genome, Human/genetics ; Histone Acetyltransferases/metabolism ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/chemistry/metabolism ; Humans ; Male ; Mice ; Mutant Proteins/genetics/metabolism ; Mutation/*genetics ; Myeloid-Lymphoid Leukemia Protein/metabolism ; Neoplasms/*genetics/metabolism/*pathology ; Phenotype ; Protein Binding ; Protein Processing, Post-Translational ; Tumor Suppressor Protein p53/*genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2016-01-02
    Description: Eusocial insects organize themselves into behavioral castes whose regulation has been proposed to involve epigenetic processes, including histone modification. In the carpenter ant Camponotus floridanus, morphologically distinct worker castes called minors and majors exhibit pronounced differences in foraging and scouting behaviors. We found that these behaviors are regulated by histone acetylation likely catalyzed by the conserved acetyltransferase CBP. Transcriptome and chromatin analysis in brains of scouting minors fed pharmacological inhibitors of CBP and histone deacetylases (HDACs) revealed hundreds of genes linked to hyperacetylated regions targeted by CBP. Majors rarely forage, but injection of a HDAC inhibitor or small interfering RNAs against the HDAC Rpd3 into young major brains induced and sustained foraging in a CBP-dependent manner. Our results suggest that behavioral plasticity in animals may be regulated in an epigenetic manner via histone modification.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Simola, Daniel F -- Graham, Riley J -- Brady, Cristina M -- Enzmann, Brittany L -- Desplan, Claude -- Ray, Anandasankar -- Zwiebel, Laurence J -- Bonasio, Roberto -- Reinberg, Danny -- Liebig, Jurgen -- Berger, Shelley L -- 2009005/Howard Hughes Medical Institute/ -- DP2MH107055/DP/NCCDPHP CDC HHS/ -- T32HD083185/HD/NICHD NIH HHS/ -- New York, N.Y. -- Science. 2016 Jan 1;351(6268):aac6633. doi: 10.1126/science.aac6633.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Program in Epigenetics, University of Pennsylvania, Philadelphia, PA 19104, USA. simola@upenn.edu danny.reinberg@nyumc.org juergen.liebig@asu.edu bergers@upenn.edu. ; Program in Epigenetics, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA. ; Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Program in Epigenetics, University of Pennsylvania, Philadelphia, PA 19104, USA. ; School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA. ; Department of Biology, New York University, New York, NY 10003, USA. ; Department of Entomology, University of California, Riverside, CA 92521, USA. ; Department of Biological Sciences, Vanderbilt University, Nashville, TN 37232, USA. ; Department of Molecular Pharmacology and Biochemistry, New York University School of Medicine, New York, NY 10016, USA. simola@upenn.edu danny.reinberg@nyumc.org juergen.liebig@asu.edu bergers@upenn.edu. ; School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA. simola@upenn.edu danny.reinberg@nyumc.org juergen.liebig@asu.edu bergers@upenn.edu. ; Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Program in Epigenetics, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. simola@upenn.edu danny.reinberg@nyumc.org juergen.liebig@asu.edu bergers@upenn.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26722000" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Animals ; Ants/drug effects/*genetics/*physiology ; *Behavior, Animal ; Chromatin/metabolism ; *Epigenesis, Genetic ; Histone Deacetylase 2/antagonists & inhibitors/genetics/*physiology ; Histone Deacetylase Inhibitors/pharmacology ; Protein Processing, Post-Translational ; *Social Behavior ; Social Class ; Transcriptome
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
    Call number: QZ266.8:15
    Keywords: Cancer / Gene therapy ; Histones ; Histone Code ; Neoplasms / therapy
    Pages: xiv, 209 p. : ill. (some col.)
    ISBN: 3540278575
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  • 6
    Publication Date: 2018-04-25
    Description: The metabolite acetyl-coenzyme A (acetyl-CoA) is the required acetyl donor for lysine acetylation and thereby links metabolism, signaling, and epigenetics. Nutrient availability alters acetyl-CoA levels in cancer cells, correlating with changes in global histone acetylation and gene expression. However, the specific molecular mechanisms through which acetyl-CoA production impacts gene expression and its functional roles in promoting malignant phenotypes are poorly understood. Here, using histone H3 Lys27 acetylation (H3K27ac) ChIP-seq (chromatin immunoprecipitation [ChIP] coupled with next-generation sequencing) with normalization to an exogenous reference genome (ChIP-Rx), we found that changes in acetyl-CoA abundance trigger site-specific regulation of H3K27ac, correlating with gene expression as opposed to uniformly modulating this mark at all genes. Genes involved in integrin signaling and cell adhesion were identified as acetyl-CoA-responsive in glioblastoma cells, and we demonstrate that ATP citrate lyase (ACLY)-dependent acetyl-CoA production promotes cell migration and adhesion to the extracellular matrix. Mechanistically, the transcription factor NFAT1 (nuclear factor of activated T cells 1) was found to mediate acetyl-CoA-dependent gene regulation and cell adhesion. This occurs through modulation of Ca 2+ signals, triggering NFAT1 nuclear translocation when acetyl-CoA is abundant. The findings of this study thus establish that acetyl-CoA impacts H3K27ac at specific loci, correlating with gene expression, and that expression of cell adhesion genes are driven by acetyl-CoA in part through activation of Ca 2+ –NFAT signaling.
    Print ISSN: 0890-9369
    Topics: Biology
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  • 7
    Publication Date: 2018-02-16
    Description: Epithelial tissues rely on a highly coordinated balance between self-renewal, proliferation, and differentiation, disruption of which may drive carcinogenesis. The epigenetic regulator KMT2D ( MLL4 ) is one of the most frequently mutated genes in all cancers, particularly epithelial cancers, yet its normal function in these tissues is unknown. Here, we identify a novel role for KMT2D in coordinating this fine balance, as depletion of KMT2D from undifferentiated epidermal keratinocytes results in reduced proliferation, premature spurious activation of terminal differentiation genes, and disorganized epidermal stratification. Genome-wide, KMT2D interacts with p63 and is enriched at its target enhancers. Depletion of KMT2D results in a broad loss of enhancer histone modifications H3 Lys 4 (H3K4) monomethylation (H3K4me1) and H3K27 acetylation (H3K27ac) as well as reduced expression of p63 target genes, including key genes involved in epithelial development and adhesion. Together, these results reveal a critical role for KMT2D in the control of epithelial enhancers and p63 target gene expression, including the requirement of KMT2D for the maintenance of epithelial progenitor gene expression and the coordination of proper terminal differentiation.
    Print ISSN: 0890-9369
    Topics: Biology
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