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Proc Natl Acad Sci U S A. 2017 Dec 12;114(50):13296-13301. doi: 10.1073/pnas.1714227114. Epub 2017 Nov 22.

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

Author information

1
Laboratory of Lymphocyte Biology, The Rockefeller University, New York, NY 10065.
2
The Rockefeller Graduate Program, The Rockefeller University, New York, NY 10065.
3
The Tri-Institutional MD-PhD Program, The Rockefeller University, New York, NY 10065.
4
Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, NY 10065.
5
Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, NY 10065.
6
Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, 141 57 Huddinge, Sweden.
7
The Neuroimmunology and Inflammation Program, The Rockefeller University, New York, NY 10065.
8
Division of Immune Diversity, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
9
Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065 mcewen@mail.rockefeller.edu n.papavasiliou@dkfz-heidelberg.de.
10
Laboratory of Lymphocyte Biology, The Rockefeller University, New York, NY 10065; mcewen@mail.rockefeller.edu n.papavasiliou@dkfz-heidelberg.de.

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.

KEYWORDS:

APOBEC1; RNA; editing; epitranscriptomics; monocytes

PMID:
29167373
PMCID:
PMC5740640
DOI:
10.1073/pnas.1714227114
[Indexed for MEDLINE]
Free PMC Article

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