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Nat Immunol. 2018 Oct;19(10):1137-1145. doi: 10.1038/s41590-018-0208-x. Epub 2018 Sep 17.

The effect of cellular context on miR-155-mediated gene regulation in four major immune cell types.

Hsin JP1,2,3, Lu Y4,5, Loeb GB1,2,3,6, Leslie CS7, Rudensky AY8,9,10.

Author information

1
Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
3
Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4
Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
5
Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
6
Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
7
Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. cleslie@cbio.mskcc.org.
8
Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. rudenska@mskcc.org.
9
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. rudenska@mskcc.org.
10
Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA. rudenska@mskcc.org.

Abstract

Numerous microRNAs and their target mRNAs are coexpressed across diverse cell types. However, it is unknown whether they are regulated in a manner independent of or dependent on cellular context. Here, we explored transcriptome-wide targeting and gene regulation by miR-155, whose activation-induced expression plays important roles in innate and adaptive immunity. Through mapping of miR-155 targets through differential iCLIP, mRNA quantification with RNA-seq, and 3' untranslated region (UTR)-usage analysis with poly(A)-seq in macrophages, dendritic cells, and T and B lymphocytes either sufficient or deficient in activated miR-155, we identified numerous targets differentially bound by miR-155. Whereas alternative cleavage and polyadenylation (ApA) contributed to differential miR-155 binding to some transcripts, in most cases, identical 3'-UTR isoforms were differentially regulated across cell types, thus suggesting ApA-independent and cellular-context-dependent miR-155-mediated gene regulation. Our study provides comprehensive maps of miR-155 regulatory networks and offers a valuable resource for dissecting context-dependent and context-independent miRNA-mediated gene regulation in key immune cell types.

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