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  • 1
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    Genome-scale DNA methylation maps of pluripotent and differentiated cells (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-07-05
    Description: DNA methylation is essential for normal development and has been implicated in many pathologies including cancer. Our knowledge about the genome-wide distribution of DNA methylation, how it changes during cellular differentiation and how it relates to histone methylation and other chromatin modifications in mammals remains limited. Here we report the generation and analysis of genome-scale DNA methylation profiles at nucleotide resolution in mammalian cells. Using high-throughput reduced representation bisulphite sequencing and single-molecule-based sequencing, we generated DNA methylation maps covering most CpG islands, and a representative sampling of conserved non-coding elements, transposons and other genomic features, for mouse embryonic stem cells, embryonic-stem-cell-derived and primary neural cells, and eight other primary tissues. Several key findings emerge from the data. First, DNA methylation patterns are better correlated with histone methylation patterns than with the underlying genome sequence context. Second, methylation of CpGs are dynamic epigenetic marks that undergo extensive changes during cellular differentiation, particularly in regulatory regions outside of core promoters. Third, analysis of embryonic-stem-cell-derived and primary cells reveals that 'weak' CpG islands associated with a specific set of developmentally regulated genes undergo aberrant hypermethylation during extended proliferation in vitro, in a pattern reminiscent of that reported in some primary tumours. More generally, the results establish reduced representation bisulphite sequencing as a powerful technology for epigenetic profiling of cell populations relevant to developmental biology, cancer and regenerative medicine.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2896277/" 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/PMC2896277/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Meissner, Alexander -- Mikkelsen, Tarjei S -- Gu, Hongcang -- Wernig, Marius -- Hanna, Jacob -- Sivachenko, Andrey -- Zhang, Xiaolan -- Bernstein, Bradley E -- Nusbaum, Chad -- Jaffe, David B -- Gnirke, Andreas -- Jaenisch, Rudolf -- Lander, Eric S -- R01 HG004401/HG/NHGRI NIH HHS/ -- R01 HG004401-02/HG/NHGRI NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- U54 HG003067-04/HG/NHGRI NIH HHS/ -- U54 HG003067-06/HG/NHGRI NIH HHS/ -- England -- Nature. 2008 Aug 7;454(7205):766-70. doi: 10.1038/nature07107. Epub 2008 Jul 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18600261" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Differentiation ; Cells, Cultured ; Conserved Sequence ; CpG Islands/genetics ; *DNA Methylation ; Embryonic Stem Cells/cytology/metabolism ; Fibroblasts/cytology ; Genome/genetics ; *Genomics ; Histones/genetics/metabolism ; Male ; Mice ; Neurons/cytology ; Pluripotent Stem Cells/*cytology/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
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    Dissecting direct reprogramming through integrative genomic analysis (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-05-30
    Description: Somatic cells can be reprogrammed to a pluripotent state through the ectopic expression of defined transcription factors. Understanding the mechanism and kinetics of this transformation may shed light on the nature of developmental potency and suggest strategies with improved efficiency or safety. Here we report an integrative genomic analysis of reprogramming of mouse fibroblasts and B lymphocytes. Lineage-committed cells show a complex response to the ectopic expression involving induction of genes downstream of individual reprogramming factors. Fully reprogrammed cells show gene expression and epigenetic states that are highly similar to embryonic stem cells. In contrast, stable partially reprogrammed cell lines show reactivation of a distinctive subset of stem-cell-related genes, incomplete repression of lineage-specifying transcription factors, and DNA hypermethylation at pluripotency-related loci. These observations suggest that some cells may become trapped in partially reprogrammed states owing to incomplete repression of transcription factors, and that DNA de-methylation is an inefficient step in the transition to pluripotency. We demonstrate that RNA inhibition of transcription factors can facilitate reprogramming, and that treatment with DNA methyltransferase inhibitors can improve the overall efficiency of the reprogramming process.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754827/" 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/PMC2754827/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mikkelsen, Tarjei S -- Hanna, Jacob -- Zhang, Xiaolan -- Ku, Manching -- Wernig, Marius -- Schorderet, Patrick -- Bernstein, Bradley E -- Jaenisch, Rudolf -- Lander, Eric S -- Meissner, Alexander -- U54 HG003067/HG/NHGRI NIH HHS/ -- U54 HG003067-04/HG/NHGRI NIH HHS/ -- England -- Nature. 2008 Jul 3;454(7200):49-55. doi: 10.1038/nature07056. Epub 2008 May 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18509334" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Azacitidine/pharmacology ; Cell Line ; Cell Lineage ; Cellular Reprogramming/*genetics ; Chromatin/metabolism ; DNA (Cytosine-5-)-Methyltransferase/antagonists & inhibitors/genetics/metabolism ; DNA Methylation ; Embryonic Stem Cells/metabolism ; Enzyme Inhibitors/pharmacology ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Genome/genetics ; *Genomics ; Mice ; Pluripotent Stem Cells/cytology/*metabolism ; Transcription Factors/deficiency/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
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    HDAC2 negatively regulates memory formation and synaptic plasticity (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-05-09
    Description: Chromatin modifications, especially histone-tail acetylation, have been implicated in memory formation. Increased histone-tail acetylation induced by inhibitors of histone deacetylases (HDACis) facilitates learning and memory in wild-type mice as well as in mouse models of neurodegeneration. Harnessing the therapeutic potential of HDACis requires knowledge of the specific HDAC family member(s) linked to cognitive enhancement. Here we show that neuron-specific overexpression of HDAC2, but not that of HDAC1, decreased dendritic spine density, synapse number, synaptic plasticity and memory formation. Conversely, Hdac2 deficiency resulted in increased synapse number and memory facilitation, similar to chronic treatment with HDACis in mice. Notably, reduced synapse number and learning impairment of HDAC2-overexpressing mice were ameliorated by chronic treatment with HDACis. Correspondingly, treatment with HDACis failed to further facilitate memory formation in Hdac2-deficient mice. Furthermore, analysis of promoter occupancy revealed an association of HDAC2 with the promoters of genes implicated in synaptic plasticity and memory formation. Taken together, our results suggest that HDAC2 functions in modulating synaptic plasticity and long-lasting changes of neural circuits, which in turn negatively regulates learning and memory. These observations encourage the development and testing of HDAC2-selective inhibitors for human diseases associated with memory impairment.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498958/" 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/PMC3498958/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guan, Ji-Song -- Haggarty, Stephen J -- Giacometti, Emanuela -- Dannenberg, Jan-Hermen -- Joseph, Nadine -- Gao, Jun -- Nieland, Thomas J F -- Zhou, Ying -- Wang, Xinyu -- Mazitschek, Ralph -- Bradner, James E -- DePinho, Ronald A -- Jaenisch, Rudolf -- Tsai, Li-Huei -- R01 DA028301/DA/NIDA NIH HHS/ -- R01 DA028301-02/DA/NIDA NIH HHS/ -- R01 NS051874/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 May 7;459(7243):55-60. doi: 10.1038/nature07925.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19424149" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Butyrates/pharmacology ; Dendritic Spines/physiology ; Electrical Synapses/*physiology ; Female ; Gene Expression Regulation ; Hippocampus/metabolism ; Histone Deacetylase 1 ; Histone Deacetylase 2 ; Histone Deacetylase Inhibitors ; Histone Deacetylases/deficiency/genetics/*metabolism ; Hydroxamic Acids/pharmacology ; Learning/drug effects ; Male ; Memory/drug effects/*physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neurons/metabolism ; Promoter Regions, Genetic/genetics ; Repressor Proteins/antagonists & inhibitors/genetics/*metabolism ; Sodium/pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-02-03
    Description: There is growing recognition that mammalian cells produce many thousands of large intergenic transcripts. However, the functional significance of these transcripts has been particularly controversial. Although there are some well-characterized examples, most (〉95%) show little evidence of evolutionary conservation and have been suggested to represent transcriptional noise. Here we report a new approach to identifying large non-coding RNAs using chromatin-state maps to discover discrete transcriptional units intervening known protein-coding loci. Our approach identified approximately 1,600 large multi-exonic RNAs across four mouse cell types. In sharp contrast to previous collections, these large intervening non-coding RNAs (lincRNAs) show strong purifying selection in their genomic loci, exonic sequences and promoter regions, with greater than 95% showing clear evolutionary conservation. We also developed a functional genomics approach that assigns putative functions to each lincRNA, demonstrating a diverse range of roles for lincRNAs in processes from embryonic stem cell pluripotency to cell proliferation. We obtained independent functional validation for the predictions for over 100 lincRNAs, using cell-based assays. In particular, we demonstrate that specific lincRNAs are transcriptionally regulated by key transcription factors in these processes such as p53, NFkappaB, Sox2, Oct4 (also known as Pou5f1) and Nanog. Together, these results define a unique collection of functional lincRNAs that are highly conserved and implicated in diverse biological processes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754849/" 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/PMC2754849/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guttman, Mitchell -- Amit, Ido -- Garber, Manuel -- French, Courtney -- Lin, Michael F -- Feldser, David -- Huarte, Maite -- Zuk, Or -- Carey, Bryce W -- Cassady, John P -- Cabili, Moran N -- Jaenisch, Rudolf -- Mikkelsen, Tarjei S -- Jacks, Tyler -- Hacohen, Nir -- Bernstein, Bradley E -- Kellis, Manolis -- Regev, Aviv -- Rinn, John L -- Lander, Eric S -- DP1 OD003958/OD/NIH HHS/ -- R01 HG004037/HG/NHGRI NIH HHS/ -- R01 HG004037-02/HG/NHGRI NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- U54 HG003067-05/HG/NHGRI NIH HHS/ -- England -- Nature. 2009 Mar 12;458(7235):223-7. doi: 10.1038/nature07672. Epub 2009 Feb 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19182780" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Cells, Cultured ; Chromatin/*genetics ; *Conserved Sequence/genetics ; DNA, Intergenic ; Exons/genetics ; Mammals/*genetics ; Mice ; Promoter Regions, Genetic/genetics ; RNA/*genetics ; Reproducibility of Results ; Transcription Factors/metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    Direct cell reprogramming is a stochastic process amenable to acceleration (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-11-10
    Description: Direct reprogramming of somatic cells into induced pluripotent stem (iPS) cells can be achieved by overexpression of Oct4, Sox2, Klf4 and c-Myc transcription factors, but only a minority of donor somatic cells can be reprogrammed to pluripotency. Here we demonstrate that reprogramming by these transcription factors is a continuous stochastic process where almost all mouse donor cells eventually give rise to iPS cells on continued growth and transcription factor expression. Additional inhibition of the p53/p21 pathway or overexpression of Lin28 increased the cell division rate and resulted in an accelerated kinetics of iPS cell formation that was directly proportional to the increase in cell proliferation. In contrast, Nanog overexpression accelerated reprogramming in a predominantly cell-division-rate-independent manner. Quantitative analyses define distinct cell-division-rate-dependent and -independent modes for accelerating the stochastic course of reprogramming, and suggest that the number of cell divisions is a key parameter driving epigenetic reprogramming to pluripotency.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789972/" 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/PMC2789972/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hanna, Jacob -- Saha, Krishanu -- Pando, Bernardo -- van Zon, Jeroen -- Lengner, Christopher J -- Creyghton, Menno P -- van Oudenaarden, Alexander -- Jaenisch, Rudolf -- R01 CA087869/CA/NCI NIH HHS/ -- R01 CA087869-09/CA/NCI NIH HHS/ -- R01 HD045022/HD/NICHD NIH HHS/ -- R01 HD045022-06/HD/NICHD NIH HHS/ -- R01-CA087869/CA/NCI NIH HHS/ -- R01-HDO45022/PHS HHS/ -- R37 CA084198/CA/NCI NIH HHS/ -- R37 CA084198-09/CA/NCI NIH HHS/ -- R37-CA084198/CA/NCI NIH HHS/ -- U54CA143874/CA/NCI NIH HHS/ -- England -- Nature. 2009 Dec 3;462(7273):595-601. doi: 10.1038/nature08592. Epub 2009 Nov 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA. Hanna@wi.mit.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19898493" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Differentiation ; Cell Division ; Cell Line ; *Cellular Reprogramming ; Gene Expression Regulation, Developmental ; Mice ; Mice, SCID ; Models, Biological ; Pluripotent Stem Cells/*cytology/*metabolism ; Time Factors ; Transcription Factors/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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  • 6
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    Antigen-specific B-cell receptor sensitizes B cells to infection by influenza virus (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-10-22
    Description: Influenza A virus-specific B lymphocytes and the antibodies they produce protect against infection. However, the outcome of interactions between an influenza haemagglutinin-specific B cell via its receptor (BCR) and virus is unclear. Through somatic cell nuclear transfer we generated mice that harbour B cells with a BCR specific for the haemagglutinin of influenza A/WSN/33 virus (FluBI mice). Their B cells secrete an immunoglobulin gamma 2b that neutralizes infectious virus. Whereas B cells from FluBI and control mice bind equivalent amounts of virus through interaction of haemagglutinin with surface-disposed sialic acids, the A/WSN/33 virus infects only the haemagglutinin-specific B cells. Mere binding of virus is not sufficient for infection of B cells: this requires interactions of the BCR with haemagglutinin, causing both disruption of antibody secretion and FluBI B-cell death within 18 h. In mice infected with A/WSN/33, lung-resident FluBI B cells are infected by the virus, thus delaying the onset of protective antibody release into the lungs, whereas FluBI cells in the draining lymph node are not infected and proliferate. We propose that influenza targets and kills influenza-specific B cells in the lung, thus allowing the virus to gain purchase before the initiation of an effective adaptive response.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863936/" 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/PMC3863936/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dougan, Stephanie K -- Ashour, Joseph -- Karssemeijer, Roos A -- Popp, Maximilian W -- Avalos, Ana M -- Barisa, Marta -- Altenburg, Arwen F -- Ingram, Jessica R -- Cragnolini, Juan Jose -- Guo, Chunguang -- Alt, Frederick W -- Jaenisch, Rudolf -- Ploegh, Hidde L -- DP1 GM106409/GM/NIGMS NIH HHS/ -- R01 AI033456/AI/NIAID NIH HHS/ -- R01 AI087879/AI/NIAID NIH HHS/ -- R01 GM100518/GM/NIGMS NIH HHS/ -- R01 HD045022/HD/NICHD NIH HHS/ -- R37 HD045022/HD/NICHD NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Nov 21;503(7476):406-9. doi: 10.1038/nature12637. Epub 2013 Oct 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24141948" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies/immunology/metabolism ; Antibody Specificity/immunology ; B-Lymphocytes/*immunology/pathology/secretion/*virology ; Cell Death ; Female ; Hemagglutinin Glycoproteins, Influenza Virus/immunology/metabolism ; Immunoglobulin G/immunology/metabolism ; Lung/cytology/immunology/secretion/virology ; Lymph Nodes/cytology/immunology ; Male ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Neutralization Tests ; Nuclear Transfer Techniques ; Orthomyxoviridae/pathogenicity/*physiology ; Receptors, Antigen, B-Cell/*immunology/metabolism ; Virus Replication
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  • 7
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    Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-08-19
    Description: T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy with a dismal overall prognosis, including a relapse rate of up to 25%, mainly because of the lack of non-cytotoxic targeted therapy options. Drugs that target the function of key epigenetic factors have been approved in the context of haematopoietic disorders, and mutations that affect chromatin modulators in a variety of leukaemias have recently been identified; however, 'epigenetic' drugs are not currently used for T-ALL treatment. Recently, we described that the polycomb repressive complex 2 (PRC2) has a tumour-suppressor role in T-ALL. Here we delineated the role of the histone 3 lysine 27 (H3K27) demethylases JMJD3 and UTX in T-ALL. We show that JMJD3 is essential for the initiation and maintenance of T-ALL, as it controls important oncogenic gene targets by modulating H3K27 methylation. By contrast, we found that UTX functions as a tumour suppressor and is frequently genetically inactivated in T-ALL. Moreover, we demonstrated that the small molecule inhibitor GSKJ4 (ref. 5) affects T-ALL growth, by targeting JMJD3 activity. These findings show that two proteins with a similar enzymatic function can have opposing roles in the context of the same disease, paving the way for treating haematopoietic malignancies with a new category of epigenetic inhibitors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209203/" 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/PMC4209203/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ntziachristos, Panagiotis -- Tsirigos, Aristotelis -- Welstead, G Grant -- Trimarchi, Thomas -- Bakogianni, Sofia -- Xu, Luyao -- Loizou, Evangelia -- Holmfeldt, Linda -- Strikoudis, Alexandros -- King, Bryan -- Mullenders, Jasper -- Becksfort, Jared -- Nedjic, Jelena -- Paietta, Elisabeth -- Tallman, Martin S -- Rowe, Jacob M -- Tonon, Giovanni -- Satoh, Takashi -- Kruidenier, Laurens -- Prinjha, Rab -- Akira, Shizuo -- Van Vlierberghe, Pieter -- Ferrando, Adolfo A -- Jaenisch, Rudolf -- Mullighan, Charles G -- Aifantis, Iannis -- 1R01CA105129/CA/NCI NIH HHS/ -- 1R01CA133379/CA/NCI NIH HHS/ -- 1R01CA149655/CA/NCI NIH HHS/ -- 5 T32 CA009161-37/CA/NCI NIH HHS/ -- 5P30CA16087-31/CA/NCI NIH HHS/ -- 5R01CA169784/CA/NCI NIH HHS/ -- 5R01CA173636/CA/NCI NIH HHS/ -- K99 CA188293/CA/NCI NIH HHS/ -- K99CA188293/CA/NCI NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- P30 CA016087/CA/NCI NIH HHS/ -- P30 CA016087-30/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- R01 CA105129/CA/NCI NIH HHS/ -- R01 CA133379/CA/NCI NIH HHS/ -- R01 CA149655/CA/NCI NIH HHS/ -- R01 CA173636/CA/NCI NIH HHS/ -- R01CA120196/CA/NCI NIH HHS/ -- R37 HD045022/HD/NICHD NIH HHS/ -- R37-HD04502/HD/NICHD NIH HHS/ -- U10 CA180820/CA/NCI NIH HHS/ -- U10 CA180827/CA/NCI NIH HHS/ -- U10 CA21115/CA/NCI NIH HHS/ -- U24 CA114737/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Oct 23;514(7523):513-7. doi: 10.1038/nature13605. Epub 2014 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA [2] NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, New York 10016, USA [3]. ; 1] Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA [2] Center for Health Informatics and Bioinformatics, NYU School of Medicine, New York, New York 10016, USA [3]. ; 1] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3]. ; 1] Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA [2] NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, New York 10016, USA. ; Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA. ; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Montefiore Medical Center North, Bronx, New York, New York 10467, USA. ; Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; 1] Technion, Israel Institute of Technology, Haifa 31096, Israel [2] Shaare Zedek Medical Center, Jerusalem 9103102, Israel. ; Functional Genomics of Cancer Unit, Division of Molecular Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, 20132 Milan, Italy. ; 1] Laboratory of Host Defense, WPI Immunology Frontier Research Center (WPI IFReC), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan [2] Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, 3-1Yamada-oka, Suita, Osaka 565-0871, Japan. ; Epinova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Medicines Research Centre, GunnelsWood Road, Stevenage SG1 2NY, UK. ; 1] Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA [2] Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium. ; 1] Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA [2] Department of Pathology, Columbia University Medical Center, New York, New York 10032, USA [3] Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA. ; 1] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25132549" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Benzazepines/pharmacology ; Epigenesis, Genetic/drug effects ; Histone Demethylases/genetics/*metabolism ; Histones/chemistry/metabolism ; Jumonji Domain-Containing Histone Demethylases/antagonists & ; inhibitors/*metabolism ; Lysine/metabolism ; Methylation/drug effects ; Mice ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug ; therapy/*enzymology/genetics/pathology ; Pyrimidines/pharmacology ; Tumor Suppressor Proteins/genetics/metabolism
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    Parkinson-associated risk variant in distal enhancer of alpha-synuclein modulates target gene expression (2016)
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    Publication Date: 2016-04-21
    Description: Genome-wide association studies (GWAS) have identified numerous genetic variants associated with complex diseases, but mechanistic insights are impeded by a lack of understanding of how specific risk variants functionally contribute to the underlying pathogenesis. It has been proposed that cis-acting effects of non-coding risk variants on gene expression are a major factor for phenotypic variation of complex traits and disease susceptibility. Recent genome-scale epigenetic studies have highlighted the enrichment of GWAS-identified variants in regulatory DNA elements of disease-relevant cell types. Furthermore, single nucleotide polymorphism (SNP)-specific changes in transcription factor binding are correlated with heritable alterations in chromatin state and considered a major mediator of sequence-dependent regulation of gene expression. Here we describe a novel strategy to functionally dissect the cis-acting effect of genetic risk variants in regulatory elements on gene expression by combining genome-wide epigenetic information with clustered regularly-interspaced short palindromic repeats (CRISPR)/Cas9 genome editing in human pluripotent stem cells. By generating a genetically precisely controlled experimental system, we identify a common Parkinson's disease associated risk variant in a non-coding distal enhancer element that regulates the expression of alpha-synuclein (SNCA), a key gene implicated in the pathogenesis of Parkinson's disease. Our data suggest that the transcriptional deregulation of SNCA is associated with sequence-dependent binding of the brain-specific transcription factors EMX2 and NKX6-1. This work establishes an experimental paradigm to functionally connect genetic variation with disease-relevant phenotypes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Soldner, Frank -- Stelzer, Yonatan -- Shivalila, Chikdu S -- Abraham, Brian J -- Latourelle, Jeanne C -- Barrasa, M Inmaculada -- Goldmann, Johanna -- Myers, Richard H -- Young, Richard A -- Jaenisch, Rudolf -- 1R01NS088538-01/NS/NINDS NIH HHS/ -- 2R01MH104610-15/MH/NIMH NIH HHS/ -- R01 NS088538/NS/NINDS NIH HHS/ -- England -- Nature. 2016 May 5;533(7601):95-9. doi: 10.1038/nature17939. Epub 2016 Apr 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Whitehead Institute, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA. ; Department of Biology, Massachusetts Institute of Technology, 31 Ames Street, Cambridge, Massachusetts 02139, USA. ; Department of Neurology, Boston University School of Medicine, Boston, Masssachusetts 02118, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27096366" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Brain/metabolism ; CRISPR-Cas Systems/genetics ; Enhancer Elements, Genetic/*genetics ; Epigenesis, Genetic/genetics ; *Gene Expression Regulation ; Genetic Engineering ; Genetic Predisposition to Disease/*genetics ; Genome, Human/genetics ; Homeodomain Proteins/metabolism ; Humans ; Models, Genetic ; Parkinson Disease/*genetics ; Pluripotent Stem Cells/metabolism ; Risk ; Transcription Factors/metabolism ; alpha-Synuclein/*genetics
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Corrigendum: Failure to replicate the STAP cell phenomenon (2015)
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    Publication Date: 2015-12-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉De Los Angeles, Alejandro -- Ferrari, Francesco -- Fujiwara, Yuko -- Mathieu, Ronald -- Lee, Soohyun -- Lee, Semin -- Tu, Ho-Chou -- Ross, Samantha -- Chou, Stephanie -- Nguyen, Minh -- Wu, Zhaoting -- Theunissen, Thorold W -- Powell, Benjamin E -- Imsoonthornruksa, Sumeth -- Chen, Jiekai -- Borkent, Marti -- Krupalnik, Vladislav -- Lujan, Ernesto -- Wernig, Marius -- Hanna, Jacob H -- Hochedlinger, Konrad -- Pei, Duanqing -- Jaenisch, Rudolf -- Deng, Hongkui -- Orkin, Stuart H -- Park, Peter J -- Daley, George Q -- Nature. 2015 Dec 16. doi: 10.1038/nature16479.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26675720" target="_blank"〉PubMed〈/a〉
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    Failure to replicate the STAP cell phenomenon (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-09-25
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉De Los Angeles, Alejandro -- Ferrari, Francesco -- Fujiwara, Yuko -- Mathieu, Ronald -- Lee, Soohyun -- Lee, Semin -- Tu, Ho-Chou -- Ross, Samantha -- Chou, Stephanie -- Nguyen, Minh -- Wu, Zhaoting -- Theunissen, Thorold W -- Powell, Benjamin E -- Imsoonthornruksa, Sumeth -- Chen, Jiekai -- Borkent, Marti -- Krupalnik, Vladislav -- Lujan, Ernesto -- Wernig, Marius -- Hanna, Jacob H -- Hochedlinger, Konrad -- Pei, Duanqing -- Jaenisch, Rudolf -- Deng, Hongkui -- Orkin, Stuart H -- Park, Peter J -- Daley, George Q -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Sep 24;525(7570):E6-9. doi: 10.1038/nature15513.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stem Cell Transplantation Program, Division of Pediatric Hematology Oncology, Children's Hospital Boston, and Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA. ; Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA. ; Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USApeter_park@hms.harvard.edu. ; Children's Hospital &Harvard Stem Cell Institute Flow Cytometry Research Facility, Children's Hospital Boston, Boston, Massachusetts 02115, USA. ; Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA. ; South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China. ; Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Boston, Massachusetts 02114, USA. ; Department of Development and Reproduction, Erasmus Medical Center, 3015 CN Rotterdam, Netherlands. ; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel. ; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA. ; College of Life Sciences and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26399835" target="_blank"〉PubMed〈/a〉
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