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      Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells

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          Abstract

          Recent molecular studies have revealed that, even when derived from a seemingly homogenous population, individual cells can exhibit substantial differences in gene expression, protein levels, and phenotypic output 15 , with important functional consequences 4, 5 . Existing studies of cellular heterogeneity, however, have typically measured only a few pre-selected RNAs 1, 2 or proteins 5, 6 simultaneously because genomic profiling methods 3 could not be applied to single cells until very recently 710 . Here, we use single-cell RNA-Seq to investigate heterogeneity in the response of bone marrow derived dendritic cells (BMDCs) to lipopolysaccharide (LPS). We find extensive, and previously unobserved, bimodal variation in mRNA abundance and splicing patterns, which we validate by RNA-fluorescence in situ hybridization (RNA-FISH) for select transcripts. In particular, hundreds of key immune genes are bimodally expressed across cells, surprisingly even for genes that are very highly expressed at the population average. Moreover, splicing patterns demonstrate previously unobserved levels of heterogeneity between cells. Some of the observed bimodality can be attributed to closely related, yet distinct, known maturity states of BMDCs; other portions reflect differences in the usage of key regulatory circuits. For example, we identify a module of 137 highly variable, yet co-regulated, antiviral response genes. Using cells from knockout mice, we show that variability in this module may be propagated through an interferon feedback circuit involving the transcriptional regulators Stat2 and Irf7. Our study demonstrates the power and promise of single-cell genomics in uncovering functional diversity between cells and in deciphering cell states and circuits.

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          Author and article information

          Journal
          0410462
          6011
          Nature
          Nature
          Nature
          0028-0836
          1476-4687
          23 April 2013
          19 May 2013
          13 June 2013
          13 December 2013
          : 498
          : 7453
          : 236-240
          Affiliations
          [1 ]Department of Chemistry and Chemical Biology and Department of Physics, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA
          [2 ]Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA
          [3 ]Department of Pathology & Center for Systems Biology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, USA
          [4 ]Center for Immunology and Inflammatory Diseases & Department of Medicine, Massachusetts General Hospital, Charlestown, MA 02129, USA
          [5 ]Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02140, USA
          Author notes
          []To whom correspondence should be addressed: Hongkun_Park@ 123456harvard.edu (HP), aregev@ 123456broadinstitute.org (AR)
          [*]

          These authors contributed equally to this work.

          Article
          NIHMS464887
          10.1038/nature12172
          3683364
          23685454

          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 Human Genome Research Institute : NHGRI
          Award ID: P50 HG006193 || HG
          Funded by: Office of the Director : NIH
          Award ID: DP2 OD002230 || OD
          Funded by: Office of the Director : NIH
          Award ID: DP1 OD003958 || OD
          Funded by: National Institute on Drug Abuse : NIDA
          Award ID: DP1 DA035083 || DA
          Funded by: National Cancer Institute : NCI
          Award ID: DP1 CA174427 || CA
          Funded by: Howard Hughes Medical Institute :
          Award ID: || HHMI_
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