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      The Microglial Sensome Revealed by Direct RNA Sequencing

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          Abstract

          Microglia, the principal neuroimmune sentinels of the brain, continuously sense changes in their environment and respond to invading pathogens, toxins and cellular debris. Microglia exhibit plasticity and can assume neurotoxic or neuroprotective priming states that determine their responses to danger. We used direct RNA sequencing, without amplification or cDNA synthesis, to determine the quantitative transcriptomes of microglia of healthy adult and aged mice. We validated our findings by fluorescent dual in-situ hybridization, unbiased proteomic analysis and quantitative PCR. We report here that microglia have a distinct transcriptomic signature and express a unique cluster of transcripts encoding proteins for sensing endogenous ligands and microbes that we term the “sensome”. With aging, sensome transcripts for endogenous ligand recognition are downregulated, whereas those involved in microbe recognition and host defense are upregulated. In addition, aging is associated with an overall increase in expression of microglial genes involved in neuroprotection.

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          Most cited references30

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          The transcriptional landscape of the yeast genome defined by RNA sequencing.

          The identification of untranslated regions, introns, and coding regions within an organism remains challenging. We developed a quantitative sequencing-based method called RNA-Seq for mapping transcribed regions, in which complementary DNA fragments are subjected to high-throughput sequencing and mapped to the genome. We applied RNA-Seq to generate a high-resolution transcriptome map of the yeast genome and demonstrated that most (74.5%) of the nonrepetitive sequence of the yeast genome is transcribed. We confirmed many known and predicted introns and demonstrated that others are not actively used. Alternative initiation codons and upstream open reading frames also were identified for many yeast genes. We also found unexpected 3'-end heterogeneity and the presence of many overlapping genes. These results indicate that the yeast transcriptome is more complex than previously appreciated.
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            Direct multiplexed measurement of gene expression with color-coded probe pairs.

            We describe a technology, the NanoString nCounter gene expression system, which captures and counts individual mRNA transcripts. Advantages over existing platforms include direct measurement of mRNA expression levels without enzymatic reactions or bias, sensitivity coupled with high multiplex capability, and digital readout. Experiments performed on 509 human genes yielded a replicate correlation coefficient of 0.999, a detection limit between 0.1 fM and 0.5 fM, and a linear dynamic range of over 500-fold. Comparison of the NanoString nCounter gene expression system with microarrays and TaqMan PCR demonstrated that the nCounter system is more sensitive than microarrays and similar in sensitivity to real-time PCR. Finally, a comparison of transcript levels for 21 genes across seven samples measured by the nCounter system and SYBR Green real-time PCR demonstrated similar patterns of gene expression at all transcript levels.
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              Molecular Classification of Cancer: Class Discovery and Class Prediction by Gene Expression Monitoring

              T. Golub (1999)
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                Author and article information

                Journal
                9809671
                21092
                Nat Neurosci
                Nat. Neurosci.
                Nature neuroscience
                1097-6256
                1546-1726
                5 November 2013
                27 October 2013
                December 2013
                01 June 2014
                : 16
                : 12
                Affiliations
                [1 ]Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
                [2 ]Department of Molecular Biology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
                [3 ]Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
                [4 ]Division of Infectious Diseases, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
                [5 ]Advanced Cell Diagnostics, Hayward, CA 94545, USA
                Author notes
                [* ]Correspondence should be addressed to: SEH ( shickman@ 123456partners.org ) or JEK ( jelkhoury@ 123456partners.org )
                Article
                NIHMS526188
                10.1038/nn.3554
                3840123
                24162652
                97c539cd-f68a-4e5c-994e-0de385c13509

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                Funding
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Award ID: R01 NS059005 || NS
                Funded by: National Institute on Aging : NIA
                Award ID: R01 AG032349 || AG
                Categories
                Article

                Neurosciences
                microglia,sensome,direct rna sequencing,aging,macrophages,classical activation,microbes,alternative activation,quantitative transcriptome

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