Abstract
Long noncoding RNAs (lncRNAs) have emerged as important regulators of diverse cellular processes, but their roles in the developing immune system are poorly understood. In this study, we analysed lncRNA expression during human B-cell development by array-based expression profiling of eleven distinct flow-sorted B-cell subsets, comprising pre-B1, pre-B2, immature, naive, memory, and plasma cells from bone marrow biopsies (n = 7), and naive, centroblast, centrocyte, memory, and plasmablast cells from tonsil tissue samples (n = 6), respectively. A remapping strategy was used to assign the array probes to 37630 gene-level probe sets, reflecting recent updates in genomic and transcriptomic databases, which enabled expression profiling of 19579 long noncoding RNAs, comprising 3947 antisense RNAs, 5277 lincRNAs, 7625 pseudogenes, and 2730 additional lncRNAs. As a first step towards inferring the functions of the identified lncRNAs in developing B-cells, we analysed their co-expression with well-characterized protein-coding genes, a method known as “guilt by association”. By using weighted gene co-expression network analysis, we identified 272 lincRNAs, 471 antisense RNAs, 376 pseudogene RNAs, and 64 lncRNAs within seven sub-networks associated with distinct stages of B-cell development, such as early B-cell development, B-cell proliferation, affinity maturation of antibody, and terminal differentiation. These data provide an important resource for future studies on the functions of lncRNAs in development of the adaptive immune response, and the pathogenesis of B-cell malignancies that originate from distinct B-cell subpopulations.
Highlights
Recent data implies that the mammalian genome is pervasively transcribed and encodes thousands of long noncoding RNAs that play distinct and specialized roles in numerous biological processes [1,2,3,4,5,6] and many diseases [7,8,9,10,11]
The array probes were reorganized into gene-specific probe sets using updated genome information, gene models and annotation [29], and by using weighted gene co-expression network analysis [30] on the expression profiles, we identified several long noncoding RNAs (lncRNAs) embedded in well-defined gene networks involved in specific stages of human B-cell development
We found highly similar sample grouping into distinct B-cell subsets based on expression from the two different classes (Baker’s gamma correlation of 0.95, Fig 3C), and even subdividing the lncRNAs into lincRNAs and antisense RNAs resulted in sample groupings that were very similar to protein-coding based sample clustering (Baker’s gamma correlation of 0.83 and 0.82, respectively, S1 Fig)
Summary
Recent data implies that the mammalian genome is pervasively transcribed and encodes thousands of long noncoding RNAs (lncRNAs) that play distinct and specialized roles in numerous biological processes [1,2,3,4,5,6] and many diseases [7,8,9,10,11]. LncRNAs lack a significant open reading frame and comprise an expanding inventory of noncoding RNAs (ncRNAs) that are longer. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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