TY - JOUR T1 - Non-coding Class Switch Recombination-related transcription in human normal and pathological immune responses JF - bioRxiv DO - 10.1101/384172 SP - 384172 AU - Helena Kuri-Magaña AU - Leonardo Collado-Torres AU - Andrew E. Jaffe AU - Humberto Valdovinos-Torres AU - Marbella Ovilla-Muñoz AU - Juan M Téllez-Sosa AU - Laura C Bonifaz Alfonzo AU - Jesùs Martinez-Barnetche Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/08/03/384172.abstract N2 - Background Antibody class switch recombination (CSR) to IgG, IgA or IgE is a hallmark of adaptive immunity, allowing antibody function diversification beyond IgM. CSR involves a deletion of the IgM/IgD constant region genes placing a new acceptor Constant (CH) gene, downstream of the VDJH exon. CSR depends on non-coding (CSRnc) transcription of donor Iμ and acceptor IH exons, located 5’ upstream of each CH coding gene. Although our knowledge of the role of CSRnc transcription has advanced greatly, its extension and importance in healthy and diseased humans is scarce.Methods We analyzed CSRnc transcription in 70,603 publicly available RNA-seq samples, including GTEx, TCGA and the Sequence Read Archive (SRA) using recount2, an online resource consisting of normalized RNA-seq gene and exon counts, as well as coverage BigWig files that can be programmatically accessed through R. CSRnc transcription was validated with a qRT-PCR assay for Iμ, Iγ3 and Iγ1 in humans in response to vaccination.Results We mapped IH transcription for the human IgH locus, including the less understood IGHD gene. CSRnc transcription was restricted to B cells and is widely distributed in normal adult tissues, but predominant in blood, spleen, MALT-containing tissues, visceral adipose tissue and some so-called “immune privileged” tissues. However, significant Iγ4 expression was found even in non-lymphoid fetal tissues. CSRnc expression in cancer tissues mimicked the expression of their normal counterparts, with notable pattern changes in some common cancer subsets. CSRnc transcription in tumors appears to result from tumor infiltration by B cells, since CSRnc transcription was not detected in corresponding tumor-derived immortal cell lines. Additionally, significantly increased I5 transcription in ileal mucosa in Crohn’s disease with ulceration was found.Conclusions CSRnc transcription occurs in multiple anatomical locations beyond classical secondary lymphoid organs, representing a potentially useful marker of effector B cell responses in normal and pathological immune responses. The pattern of IH exon expression may reveal clues of the local immune response (i.e. cytokine milieu) in health and disease. This is a great example of how the public recount2 data can be used to further our understanding of transcription, including regions outside the known transcriptome.AbbreviationsAIDActivated-Induced Cytidine DeaminaseCDCrohn’s diseaseCSRncClass Switch Recombination non-codingCSRClass Switch RecombinationCGGerminal CenterCHHeavy chain ConstantELSEctopic Lymphoid StructuresEBVEpstein Barr VirusGTExGenotype-Tissue Expression ProjectIHI exonMALTMucosal Associated lymphoid TissuePAMPPathogen-Associated Molecular PatternPBPeripheral bloodSRASequence Read ArchiveRPKMReads Per Kilobase (transcript) Per Million (reads)TCGAThe Cancer Genome Atlas. ER -