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  • 1
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    Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-02-20
    Description: Alzheimer's disease (AD) is a severe age-related neurodegenerative disorder characterized by accumulation of amyloid-beta plaques and neurofibrillary tangles, synaptic and neuronal loss, and cognitive decline. Several genes have been implicated in AD, but chromatin state alterations during neurodegeneration remain uncharacterized. Here we profile transcriptional and chromatin state dynamics across early and late pathology in the hippocampus of an inducible mouse model of AD-like neurodegeneration. We find a coordinated downregulation of synaptic plasticity genes and regulatory regions, and upregulation of immune response genes and regulatory regions, which are targeted by factors that belong to the ETS family of transcriptional regulators, including PU.1. Human regions orthologous to increasing-level enhancers show immune-cell-specific enhancer signatures as well as immune cell expression quantitative trait loci, while decreasing-level enhancer orthologues show fetal-brain-specific enhancer activity. Notably, AD-associated genetic variants are specifically enriched in increasing-level enhancer orthologues, implicating immune processes in AD predisposition. Indeed, increasing enhancers overlap known AD loci lacking protein-altering variants, and implicate additional loci that do not reach genome-wide significance. Our results reveal new insights into the mechanisms of neurodegeneration and establish the mouse as a useful model for functional studies of AD regulatory regions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530583/" 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/PMC4530583/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gjoneska, Elizabeta -- Pfenning, Andreas R -- Mathys, Hansruedi -- Quon, Gerald -- Kundaje, Anshul -- Tsai, Li-Huei -- Kellis, Manolis -- R01 HG004037/HG/NHGRI NIH HHS/ -- R01 NS078839/NS/NINDS NIH HHS/ -- R01HG004037-07/HG/NHGRI NIH HHS/ -- R01NS078839/NS/NINDS NIH HHS/ -- RC1 HG005334/HG/NHGRI NIH HHS/ -- RC1HG005334/HG/NHGRI NIH HHS/ -- England -- Nature. 2015 Feb 19;518(7539):365-9. doi: 10.1038/nature14252.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; 1] Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2] Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; 1] Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2] Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] Department of Genetics, Department of Computer Science, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25693568" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/*genetics/*immunology/physiopathology ; Animals ; Chromatin/genetics/metabolism ; Conserved Sequence ; Disease Models, Animal ; Down-Regulation/genetics ; Enhancer Elements, Genetic/genetics ; Epigenesis, Genetic/*genetics ; Epigenomics ; Female ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study ; Hippocampus/metabolism ; Humans ; Immunity/genetics ; Memory/physiology ; Mice ; *Models, Biological ; Neuronal Plasticity/genetics ; Polymorphism, Single Nucleotide/genetics ; Proto-Oncogene Proteins/metabolism ; Trans-Activators/metabolism ; Transcription, Genetic/genetics ; Up-Regulation/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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  • 2
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    Principles of regulatory information conservation between mouse and human (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-11-21
    Description: To broaden our understanding of the evolution of gene regulation mechanisms, we generated occupancy profiles for 34 orthologous transcription factors (TFs) in human-mouse erythroid progenitor, lymphoblast and embryonic stem-cell lines. By combining the genome-wide transcription factor occupancy repertoires, associated epigenetic signals, and co-association patterns, here we deduce several evolutionary principles of gene regulatory features operating since the mouse and human lineages diverged. The genomic distribution profiles, primary binding motifs, chromatin states, and DNA methylation preferences are well conserved for TF-occupied sequences. However, the extent to which orthologous DNA segments are bound by orthologous TFs varies both among TFs and with genomic location: binding at promoters is more highly conserved than binding at distal elements. Notably, occupancy-conserved TF-occupied sequences tend to be pleiotropic; they function in several tissues and also co-associate with many TFs. Single nucleotide variants at sites with potential regulatory functions are enriched in occupancy-conserved TF-occupied sequences.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4343047/" 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/PMC4343047/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cheng, Yong -- Ma, Zhihai -- Kim, Bong-Hyun -- Wu, Weisheng -- Cayting, Philip -- Boyle, Alan P -- Sundaram, Vasavi -- Xing, Xiaoyun -- Dogan, Nergiz -- Li, Jingjing -- Euskirchen, Ghia -- Lin, Shin -- Lin, Yiing -- Visel, Axel -- Kawli, Trupti -- Yang, Xinqiong -- Patacsil, Dorrelyn -- Keller, Cheryl A -- Giardine, Belinda -- Mouse ENCODE Consortium -- Kundaje, Anshul -- Wang, Ting -- Pennacchio, Len A -- Weng, Zhiping -- Hardison, Ross C -- Snyder, Michael P -- 1U54HG00699/HG/NHGRI NIH HHS/ -- 3RC2HG005602/HG/NHGRI NIH HHS/ -- 5U54HG006996/HG/NHGRI NIH HHS/ -- R01 DK065806/DK/NIDDK NIH HHS/ -- R01 DK096266/DK/NIDDK NIH HHS/ -- R01 ES024992/ES/NIEHS NIH HHS/ -- R01 EY021482/EY/NEI NIH HHS/ -- R01 GM083337/GM/NIGMS NIH HHS/ -- R01 HG003988/HG/NHGRI NIH HHS/ -- R01 HG004037/HG/NHGRI NIH HHS/ -- R01 HG007175/HG/NHGRI NIH HHS/ -- R01 HG007348/HG/NHGRI NIH HHS/ -- R01 HG007354/HG/NHGRI NIH HHS/ -- R01DK065806/DK/NIDDK NIH HHS/ -- R01HG003988/HG/NHGRI NIH HHS/ -- R37 DK044746/DK/NIDDK NIH HHS/ -- RC2 HG005573/HG/NHGRI NIH HHS/ -- RC2 HG005602/HG/NHGRI NIH HHS/ -- RC2HG005573/HG/NHGRI NIH HHS/ -- U01 DE024427/DE/NIDCR NIH HHS/ -- U41 HG007234/HG/NHGRI NIH HHS/ -- U54 HG006996/HG/NHGRI NIH HHS/ -- U54 HG006997/HG/NHGRI NIH HHS/ -- U54 HG006998/HG/NHGRI NIH HHS/ -- U54 HG007004/HG/NHGRI NIH HHS/ -- U54HG006997/HG/NHGRI NIH HHS/ -- England -- Nature. 2014 Nov 20;515(7527):371-5. doi: 10.1038/nature13985.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Stanford University, Stanford, California 94305, USA. ; Program in Bioinformatics and Integrative Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. ; 1] Center for Comparative Genomics and Bioinformatics, Huck Institutes of the Life Sciences, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA [2] BRCF Bioinformatics Core, University of Michigan, Ann Arbor, Michigan 48105, USA. ; Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, Missouri 63108, USA. ; Center for Comparative Genomics and Bioinformatics, Huck Institutes of the Life Sciences, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; 1] Department of Genetics, Stanford University, Stanford, California 94305, USA [2] Division of Cardiovascular Medicine, Stanford University, Stanford, California 94304, USA. ; 1] Department of Genetics, Stanford University, Stanford, California 94305, USA [2] Department of Surgery, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; 1] Lawrence Berkeley National Laboratory, Genomics Division, Berkeley, California 94701, USA [2] Department of Energy Joint Genome Institute, Walnut Creek, California 94598, USA [3] School of Natural Sciences, University of California, Merced, California 95343, USA. ; 1] Lawrence Berkeley National Laboratory, Genomics Division, Berkeley, California 94701, USA [2] Department of Energy Joint Genome Institute, Walnut Creek, California 94598, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25409826" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Chromatin/genetics/metabolism ; Conserved Sequence/*genetics ; Enhancer Elements, Genetic/genetics ; Genome/*genetics ; *Genomics ; Humans ; Mice ; Polymorphism, Single Nucleotide/genetics ; Regulatory Sequences, Nucleic Acid/*genetics ; 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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    Architecture of the human regulatory network derived from ENCODE data (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-09-08
    Description: Transcription factors bind in a combinatorial fashion to specify the on-and-off states of genes; the ensemble of these binding events forms a regulatory network, constituting the wiring diagram for a cell. To examine the principles of the human transcriptional regulatory network, we determined the genomic binding information of 119 transcription-related factors in over 450 distinct experiments. We found the combinatorial, co-association of transcription factors to be highly context specific: distinct combinations of factors bind at specific genomic locations. In particular, there are significant differences in the binding proximal and distal to genes. We organized all the transcription factor binding into a hierarchy and integrated it with other genomic information (for example, microRNA regulation), forming a dense meta-network. Factors at different levels have different properties; for instance, top-level transcription factors more strongly influence expression and middle-level ones co-regulate targets to mitigate information-flow bottlenecks. Moreover, these co-regulations give rise to many enriched network motifs (for example, noise-buffering feed-forward loops). Finally, more connected network components are under stronger selection and exhibit a greater degree of allele-specific activity (that is, differential binding to the two parental alleles). The regulatory information obtained in this study will be crucial for interpreting personal genome sequences and understanding basic principles of human biology and disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154057/" 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/PMC4154057/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gerstein, Mark B -- Kundaje, Anshul -- Hariharan, Manoj -- Landt, Stephen G -- Yan, Koon-Kiu -- Cheng, Chao -- Mu, Xinmeng Jasmine -- Khurana, Ekta -- Rozowsky, Joel -- Alexander, Roger -- Min, Renqiang -- Alves, Pedro -- Abyzov, Alexej -- Addleman, Nick -- Bhardwaj, Nitin -- Boyle, Alan P -- Cayting, Philip -- Charos, Alexandra -- Chen, David Z -- Cheng, Yong -- Clarke, Declan -- Eastman, Catharine -- Euskirchen, Ghia -- Frietze, Seth -- Fu, Yao -- Gertz, Jason -- Grubert, Fabian -- Harmanci, Arif -- Jain, Preti -- Kasowski, Maya -- Lacroute, Phil -- Leng, Jing -- Lian, Jin -- Monahan, Hannah -- O'Geen, Henriette -- Ouyang, Zhengqing -- Partridge, E Christopher -- Patacsil, Dorrelyn -- Pauli, Florencia -- Raha, Debasish -- Ramirez, Lucia -- Reddy, Timothy E -- Reed, Brian -- Shi, Minyi -- Slifer, Teri -- Wang, Jing -- Wu, Linfeng -- Yang, Xinqiong -- Yip, Kevin Y -- Zilberman-Schapira, Gili -- Batzoglou, Serafim -- Sidow, Arend -- Farnham, Peggy J -- Myers, Richard M -- Weissman, Sherman M -- Snyder, Michael -- T32 GM007205/GM/NIGMS NIH HHS/ -- T32GM008283-24/GM/NIGMS NIH HHS/ -- U01 HG004695/HG/NHGRI NIH HHS/ -- U54 HG004558/HG/NHGRI NIH HHS/ -- England -- Nature. 2012 Sep 6;489(7414):91-100. doi: 10.1038/nature11245.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut 06520, USA. mark.gerstein@yale.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22955619" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Cell Line ; DNA/*genetics ; *Encyclopedias as Topic ; GATA1 Transcription Factor/metabolism ; Gene Expression Profiling ; Gene Regulatory Networks/*genetics ; Genome, Human/*genetics ; Genomics ; Humans ; K562 Cells ; *Molecular Sequence Annotation ; Organ Specificity ; Phosphorylation/genetics ; Polymorphism, Single Nucleotide/genetics ; Protein Interaction Maps ; RNA, Untranslated/genetics/metabolism ; Regulatory Sequences, Nucleic Acid/*genetics ; Selection, Genetic/genetics ; Transcription Factors/*metabolism ; Transcription Initiation Site
    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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