Abstract
lncRNAs make up a majority of the human transcriptome and have key regulatory functions. Here we perform unbiased de novo annotation of transcripts expressed during the human humoral immune response to find 30% of the human genome transcribed during this process, yet 58% of these transcripts manifest striking differential expression, indicating an lncRNA phylogenetic relationship among cell types that is more robust than that of coding genes. We provide an atlas of lncRNAs in naive and GC B-cells that indicates their partition into ten functionally categories based on chromatin features, DNase hypersensitivity and transcription factor localization, defining lncRNAs classes such as enhancer-RNAs (eRNA), bivalent-lncRNAs, and CTCF-associated, among others. Specifically, eRNAs are transcribed in 8.6% of regular enhancers and 36.5% of super enhancers, and are associated with coding genes that participate in critical immune regulatory pathways, while plasma cells have uniquely high levels of circular-RNAs accounted for by and reflecting the combinatorial clonal state of the Immunoglobulin loci.
Highlights
LncRNAs make up a majority of the human transcriptome and have key regulatory functions
To validate the selected populations, we examined the transcript abundance of genes used for fluorescence-activated cell sorting (FACS) and observed the expected patterns of differential expression
The average expression of CD10 was 9.7-folds higher in Germinal centers (GCs) compared to naive B (NB) subpopulations, whereas CD44 was expressed at lower level in GC-derived cells vs. NB cells or bone marrow plasma cells (BMPCs) (Supplementary Fig. 3)
Summary
LncRNAs make up a majority of the human transcriptome and have key regulatory functions. Petri et al.[14] analyzed the expression of lncRNAs in 11 discrete human B cell subsets using exon array-based technology In this study, they detected 1183 lncRNAs associated with seven coding genes sub-networks related to distinct stage of B cell development, including terminal differentiation. Brazão et al.[15] reported a catalog of 4516 lncRNAs expressed across 11 mouse B cell populations, including stages of terminal B cell differentiation using the stranded polyA+ RNA-seq strategy They identified 1878 novel intergenic lncRNAs, some of which were related to histone modification marks associated with enhancer or promoter regions. These studies point to importance of fully characterizing the full transcriptome of B cells as they undergo the GC reaction and subsequent terminal differentiation. Our studies provide evidence that lncRNAs are expressed in each stage of the humoral immune response and are transcribed from specific enhancer regions related to key stage -specific phenotypedriving genes
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