期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：15
页码：E1888-E1897
DOI：10.1073/pnas.1422490112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificancePlasma cells produce immunoglobulin and provide long-lasting protective immunity. Differentiation of B cells to plasma cells is accompanied by major changes in gene expression, which are regulated at both transcriptional and posttranscriptional levels. We have used genome-wide methods to identify the binding sites and RNA targets of heterogeneous nuclear RNA-binding protein LL (hnRNPLL), whose expression is up-regulated during B-cell to plasma-cell differentiation. In addition to its recognized function in promoting exon splicing, hnRNPLL shapes the transcriptome of plasma cells by regulating exon inclusion and promoting mRNA stability. hnRNPLL binds to preferred sequences in RNA and is critical for complete plasma-cell differentiation, by mediating the down-regulation of B-cell-specific transcription factors and maximizing immunoglobulin production. 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.
