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Proc Natl Acad Sci U S A. 2015 Apr 14;112(15):E1888-97. doi: 10.1073/pnas.1422490112. Epub 2015 Mar 30.

RNA-binding protein hnRNPLL regulates mRNA splicing and stability during B-cell to plasma-cell differentiation.

Author information

1
Divisions of Signaling and Gene Expression and Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037; and.
2
Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
3
Divisions of Signaling and Gene Expression and Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037; and Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093 arao@liai.org.

Abstract

Posttranscriptional regulation is a major mechanism to rewire transcriptomes during differentiation. Heterogeneous nuclear RNA-binding protein LL (hnRNPLL) is specifically induced in terminally differentiated lymphocytes, including effector T cells and plasma cells. To study the molecular functions of hnRNPLL at a genome-wide level, we identified hnRNPLL RNA targets and binding sites in plasma cells through integrated Photoactivatable-Ribonucleoside-Enhanced Cross-Linking and Immunoprecipitation (PAR-CLIP) and RNA sequencing. hnRNPLL preferentially recognizes CA dinucleotide-containing sequences in introns and 3' untranslated regions (UTRs), promotes exon inclusion or exclusion in a context-dependent manner, and stabilizes mRNA when associated with 3' UTRs. During differentiation of primary B cells to plasma cells, hnRNPLL mediates a genome-wide switch of RNA processing, resulting in loss of B-cell lymphoma 6 (Bcl6) expression and increased Ig production--both hallmarks of plasma-cell maturation. Our data identify previously unknown functions of hnRNPLL in B-cell to plasma-cell differentiation and demonstrate that the RNA-binding protein hnRNPLL has a critical role in tuning transcriptomes of terminally differentiating B lymphocytes.

KEYWORDS:

PAR-CLIP; RNA binding proteins; alternative splicing; hnRNP; plasma cells

PMID:
25825742
PMCID:
PMC4403190
DOI:
10.1073/pnas.1422490112
[Indexed for MEDLINE]
Free PMC Article

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