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  • 1
    Publication Date: 2012-07-06
    Description: Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequently found in human glioblastomas and cytogenetically normal acute myeloid leukaemias (AML). These alterations are gain-of-function mutations in that they drive the synthesis of the 'oncometabolite' R-2-hydroxyglutarate (2HG). It remains unclear how IDH1 and IDH2 mutations modify myeloid cell development and promote leukaemogenesis. Here we report the characterization of conditional knock-in (KI) mice in which the most common IDH1 mutation, IDH1(R132H), is inserted into the endogenous murine Idh1 locus and is expressed in all haematopoietic cells (Vav-KI mice) or specifically in cells of the myeloid lineage (LysM-KI mice). These mutants show increased numbers of early haematopoietic progenitors and develop splenomegaly and anaemia with extramedullary haematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells have hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1- or IDH2-mutant AML. To our knowledge, our study is the first to describe the generation and characterization of conditional IDH1(R132H)-KI mice, and also the first report to demonstrate the induction of a leukaemic DNA methylation signature in a mouse model. Our report thus sheds light on the mechanistic links between IDH1 mutation and human AML.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005896/" 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/PMC4005896/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sasaki, Masato -- Knobbe, Christiane B -- Munger, Joshua C -- Lind, Evan F -- Brenner, Dirk -- Brustle, Anne -- Harris, Isaac S -- Holmes, Roxanne -- Wakeham, Andrew -- Haight, Jillian -- You-Ten, Annick -- Li, Wanda Y -- Schalm, Stefanie -- Su, Shinsan M -- Virtanen, Carl -- Reifenberger, Guido -- Ohashi, Pamela S -- Barber, Dwayne L -- Figueroa, Maria E -- Melnick, Ari -- Zuniga-Pflucker, Juan-Carlos -- Mak, Tak W -- R01 AI081773/AI/NIAID NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2012 Aug 30;488(7413):656-9. doi: 10.1038/nature11323.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22763442" target="_blank"〉PubMed〈/a〉
    Keywords: Aging ; Animals ; Bone Marrow/pathology ; Cell Lineage ; CpG Islands/genetics ; DNA Methylation ; Disease Models, Animal ; Epigenesis, Genetic/*genetics ; Female ; Gene Knock-In Techniques ; Glioma/pathology ; Hematopoiesis ; Hematopoietic Stem Cells/*cytology/metabolism ; Histones/metabolism ; Humans ; Isocitrate Dehydrogenase/*genetics/*metabolism ; Leukemia, Myeloid, Acute/genetics ; Male ; Mice ; Mutant Proteins/genetics/*metabolism ; Mutation/*genetics ; Myeloid Cells/cytology/metabolism ; Spleen/pathology
    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: 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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  • 3
    Publication Date: 2013-10-11
    Description: DNA methylation was first described almost a century ago; however, the rules governing its establishment and maintenance remain elusive. Here we present data demonstrating that active transcription regulates levels of genomic methylation. We identify a novel RNA arising from the CEBPA gene locus that is critical in regulating the local DNA methylation profile. This RNA binds to DNMT1 and prevents CEBPA gene locus methylation. Deep sequencing of transcripts associated with DNMT1 combined with genome-scale methylation and expression profiling extend the generality of this finding to numerous gene loci. Collectively, these results delineate the nature of DNMT1-RNA interactions and suggest strategies for gene-selective demethylation of therapeutic targets in human diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870304/" 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/PMC3870304/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Di Ruscio, Annalisa -- Ebralidze, Alexander K -- Benoukraf, Touati -- Amabile, Giovanni -- Goff, Loyal A -- Terragni, Jolyon -- Figueroa, Maria Eugenia -- De Figueiredo Pontes, Lorena Lobo -- Alberich-Jorda, Meritxell -- Zhang, Pu -- Wu, Mengchu -- D'Alo, Francesco -- Melnick, Ari -- Leone, Giuseppe -- Ebralidze, Konstantin K -- Pradhan, Sriharsa -- Rinn, John L -- Tenen, Daniel G -- CA118316/CA/NCI NIH HHS/ -- CA66996/CA/NCI NIH HHS/ -- HL56745/HL/NHLBI NIH HHS/ -- P01 CA066996/CA/NCI NIH HHS/ -- R01 CA118316/CA/NCI NIH HHS/ -- R01 HL056745/HL/NHLBI NIH HHS/ -- R01 HL112719/HL/NHLBI NIH HHS/ -- T32 HL007917-11A1/HL/NHLBI NIH HHS/ -- England -- Nature. 2013 Nov 21;503(7476):371-6. doi: 10.1038/nature12598. Epub 2013 Oct 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA [3] Universita Cattolica del Sacro Cuore, Institute of Hematology, L.go A. Gemelli 8, Rome 00168, Italy [4].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24107992" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; CCAAT-Enhancer-Binding Proteins/*genetics ; Cell Line ; DNA/genetics/metabolism ; DNA (Cytosine-5-)-Methyltransferase/*metabolism ; DNA Methylation/*genetics ; Gene Expression Profiling ; Gene Expression Regulation/*genetics ; Genome, Human/genetics ; Humans ; RNA, Messenger/genetics/metabolism ; RNA, Untranslated/genetics/*metabolism ; RNA-Binding Proteins/metabolism ; Substrate Specificity ; Transcription, 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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  • 4
    ISSN: 1573-5052
    Keywords: Clonal growth ; Density-dependence ; Salt-marsh succession ; Sediment accretion ; Tiller demography ; Vegetation zonation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Tiller demography was compared in two populations of Spartina maritima present at similar elevations in the coastal saltmarshes of Odiel (Huelva, S.W. Spain). The successional population consisted of colonizing tussocks in a littoral lagoon, and the non-successional population comprised a stable sward that had fringed a major channel for 40 years. At both sites S. maritima was replaced by Arthrocnemum perenne at higher elevation, where sediments were less reducing. Rapid, consistent sediment accretion confirmed the successional nature of the lagoon site but there was little net accretion in the stable sward. Census of permanent quadrats at the successional site chronicled moving concentric ‘waves’ of high tiller density as tussocks expanded. Initially high densities declined after one year to low values at the end of the second year but they had almost recovered after 3 years. The decline represented a combination of reduced numbers of births and increased numbers of deaths. Tiller densities were substantially higher in the stable sward and showed relatively small fluctuations with time. The underlying risk of tiller mortality was similar in the two populations for much of the time but after two years there was increased mortality, mainly associated with flowering, at the successional site; very few tillers flowered in the sward. This mortality contributed to a shift to a younger age structure in the successional population. Data aggregated over consecutive 3-monthly periods were examined for density dependence. None was found in the successional population. In the sward population there was evidence of density-dependent adult and juvenile mortality of tillers, particularly over the first 18 months of the study, when there were compensatory responses to subtle variations in density. The lack of density dependence and relatively low peak density of about 2000 m-2 near to the leading edges of the expanding tussocks at the successional site suggest that tiller placement there was regulated mainly by physiological mechanisms affecting rhizome growth and bud development in well integrated clones.
    Type of Medium: Electronic Resource
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