title: Ubiquitously transcribed genes use alternative polyadenylation to achieve tissue-specific expression.
abstract: More than half of human genes use alternative cleavage and polyadenylation (ApA) to generate mRNA transcripts that differ in the lengths of their 3' untranslated regions (UTRs), thus altering the post-transcriptional fate of the message and likely the protein output. The extent of 3' UTR variation across tissues and the functional role of ApA remain poorly understood. We developed a sequencing method called 3'-seq to quantitatively map the 3' ends of the transcriptome of diverse human tissues and isogenic transformation systems. We found that cell type-specific gene expression is accomplished by two complementary programs. Tissue-restricted genes tend to have single 3' UTRs, whereas a majority of ubiquitously transcribed genes generate multiple 3' UTRs. During transformation and differentiation, single-UTR genes change their mRNA abundance levels, while multi-UTR genes mostly change 3' UTR isoform ratios to achieve tissue specificity. However, both regulation programs target genes that function in the same pathways and processes that characterize the new cell type. Instead of finding global shifts in 3' UTR length during transformation and differentiation, we identify tissue-specific groups of multi-UTR genes that change their 3' UTR ratios; these changes in 3' UTR length are largely independent from changes in mRNA abundance. Finally, tissue-specific usage of ApA sites appears to be a mechanism for changing the landscape targetable by ubiquitously expressed microRNAs.
authors.affiliation: Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Steve
authors.initials: S
authors.lastname: Lianoglou
authors.forename: Vidur
authors.initials: V
authors.lastname: Garg
authors.forename: Julie L
authors.initials: JL
authors.lastname: Yang
authors.forename: Christina S
authors.initials: CS
authors.lastname: Leslie
authors.forename: Christine
authors.initials: C
authors.lastname: Mayr
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral / Q000502:physiology; D053595:Embryonic Stem Cells / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006367:HeLa Cells; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D061986:MCF-7 Cells; D008969:Molecular Sequence Data; D009928:Organ Specificity / Q000235:genetics; D026723:Polyadenylation; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D020033:Protein Isoforms; D012333:RNA, Messenger
keywords: 3′ UTR isoform; alternative polyadenylation; computational biology; gene regulation; tissue-specific regulation of gene expression; transcriptome analysis