GSE111310
Widespread intronic polyadenylation diversifies immune cell transcriptomes
Alternative cleavage and polyadenylation (ApA) can generate mRNA isoforms with differences in 3'UTR length without changing the coding region (CDR). However, ApA can also recognize intronic polyadenylation (IpA) signals to generate transcripts that lose part or all of the CDR. We analyzed 46 3'-seq and RNA-seq profiles from normal human tissues, primary immune cells, and multiple myeloma (MM) samples and created an atlas of 4,927 high confidence IpA events represented in these cell types. Up to 16% of expressed genes in immune cells generate IpA isoforms, a majority of which are differentially used during B cell development or in different cellular environments, while MM cells display a striking loss of IpA isoforms expressed in plasma cells (PCs), their cell type of origin. IpA events can lead to truncated proteins lacking C-terminal functional domains. This can mimic ectodomain shedding through loss of transmembrane domains or alter the binding specificity of proteins with DNA-binding or protein-protein interaction domains, thus contributing to diversification of the transcriptome.  In MM, loss of expression of PC IpA isoforms is associated with shorter progression-free survival and impacts key genes in MM biology and response to the therapeutic lenalidomide, including those encoding the transcription factor IKZF1 and core E3 ubiquitin ligase complex component CUL4A. Overall design: Examination of IpA isoforms in primary immune cells and patients with multiple myeloma (MM). The study is primarily focused on 3'-seq samples: 29 samples from current study 17 samples from SRP029953 There are also 18 RNA-seq experiments which were used for verification of IpA events focusing in the introns of the genes.