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  • 1
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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
    Published by Nature Publishing Group (NPG)
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  • 2
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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
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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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
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 4
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    Parkinson-associated risk variant in distal enhancer of alpha-synuclein modulates target gene expression (2016)
    Nature Publishing Group (NPG)
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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
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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