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Epitranscriptomic profiling across cell types reveals associations between APOBEC1-mediated RNA editing, gene expression outcomes, and cellular function

  1. F. Nina Papavasilioua,h,3
  1. aLaboratory of Lymphocyte Biology, The Rockefeller University, New York, NY 10065;
  2. bThe Rockefeller Graduate Program, The Rockefeller University, New York, NY 10065;
  3. cThe Tri-Institutional MD-PhD Program, The Rockefeller University, New York, NY 10065;
  4. dLaboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, NY 10065;
  5. eLaboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, NY 10065;
  6. fDepartment of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, 141 57 Huddinge, Sweden;
  7. gThe Neuroimmunology and Inflammation Program, The Rockefeller University, New York, NY 10065;
  8. hDivision of Immune Diversity, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;
  9. iHarold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065
  1. Contributed by Bruce S. McEwen, October 30, 2017 (sent for review August 14, 2017; reviewed by Silvo Conticello and Jin Billy Li)

Significance

RNA editing is an enzymatic modification that leads to single-nucleotide changes in mRNA. Editing is particularly robust within cells of the immune lineage. Here, we focus on the macrophage and demonstrate that genetic inactivation of the RNA-editing enzyme Apobec1 affects protein levels of genes that underlie macrophage-specific behaviors including phagocytosis and transendothelial migration. We further show that loss of Apobec1 leads to an overabundance of proinflammatory monocytes, a hallmark of many chronic diseases. These data provide the first view of the consequences of editing for gene expression and cellular function. Overall, epitranscriptomic changes catalyzed by RNA editing might be important biomarkers of diseases associated with inflammation (e.g., neurodegenerative diseases), for which an association with DNA mutation has been lacking.

Abstract

Epitranscriptomics refers to posttranscriptional alterations on an mRNA sequence that are dynamic and reproducible, and affect gene expression in a similar way to epigenetic modifications. However, the functional relevance of those modifications for the transcript, the cell, and the organism remain poorly understood. Here, we focus on RNA editing and show that Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-1 (APOBEC1), together with its cofactor RBM47, mediates robust editing in different tissues. The majority of editing events alter the sequence of the 3′UTR of targeted transcripts, and we focus on one cell type (monocytes) and on a small set of highly edited transcripts within it to show that editing alters gene expression by modulating translation (but not RNA stability or localization). We further show that specific cellular processes (phagocytosis and transendothelial migration) are enriched for transcripts that are targets of editing and that editing alters their function. Finally, we survey bone marrow progenitors and demonstrate that common monocyte progenitor cells express high levels of APOBEC1 and are susceptible to loss of the editing enzyme. Overall, APOBEC1-mediated transcriptome diversification is required for the fine-tuning of protein expression in monocytes, suggesting an epitranscriptomic mechanism for the proper maintenance of homeostasis in innate immune cells.

Footnotes

  • ?1V.R.-E. and D.H. contributed equally to this work.

  • ?2Present address: B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, MD 20892.

  • ?3To whom correspondence may be addressed. Email: mcewen{at}mail.rockefeller.edu or n.papavasiliou{at}dkfz-heidelberg.de.
  • Author contributions: V.R.-E., D.H., C.E.H., K.B., K.G., B.S.M., and F.N.P. designed research; V.R.-E., D.H., C.E.H., Y.A.B., E.C.G., K.G., and F.N.P. performed research; V.R.-E., E.C.G., T.P.S., S.H., and F.N.P. contributed new reagents/analytic tools; V.R.-E., D.H., C.E.H., Y.A.B., K.G., and F.N.P. analyzed data; and V.R.-E., D.H., K.B., and F.N.P. wrote the paper.

  • Reviewers: S.C., Istituto Toscano Tumori; and J.B.L., Stanford University.

  • The authors declare no conflict of interest.

  • Data deposition: The sequence reported in this paper has been deposited in the National Center for Biotechnology Information Sequence Read Archive (accession no. GSE58798).

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1714227114/-/DCSupplemental.

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