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Nat Commun. 2018 Apr 30;9(1):1716. doi: 10.1038/s41467-018-04112-z.

Widespread intronic polyadenylation diversifies immune cell transcriptomes.

Author information

1
Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Tri-I Program in Computational Biology and Medicine, Weill Cornell Graduate College, New York, NY 10065, USA.
3
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
4
Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
5
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. mayrc@mskcc.org.
6
Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. cleslie@cbio.mskcc.org.

Abstract

Alternative cleavage and polyadenylation (ApA) is known to alter untranslated region (3'UTR) length but can also recognize intronic polyadenylation (IpA) signals to generate transcripts that lose part or all of the coding region. We analyzed 46 3'-seq and RNA-seq profiles from normal human tissues, primary immune cells, and multiple myeloma (MM) samples and created an atlas of 4927 high-confidence IpA events represented in these cell types. IpA isoforms are widely expressed in immune cells, differentially used during B-cell development or in different cellular environments, and can generate truncated proteins lacking C-terminal functional domains. This can mimic ectodomain shedding through loss of transmembrane domains or alter the binding specificity of proteins with DNA-binding or protein-protein interaction domains. MM cells display a striking loss of IpA isoforms expressed in plasma cells, associated with shorter progression-free survival and impacting key genes in MM biology and response to lenalidomide.

PMID:
29712909
PMCID:
PMC5928244
DOI:
10.1038/s41467-018-04112-z
[Indexed for MEDLINE]
Free PMC Article

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