Regulation of Intronic Polyadenylation by PCF11 Impacts mRNA Expression of Long Genes

Abstract

Summary: Regulation of cleavage and polyadenylation (CPA) affects gene expression and polyadenylation site (PAS) choice. Here, we report that the CPA and termination factor PCF11 modulates gene expression on the basis of gene size. Although downregulation of PCF11 leads to inhibition of short gene expression, long genes are upregulated because of suppressed intronic polyadenylation (IPA) enriched in large introns. We show that this regulatory scheme, named PCF11-mediated expression regulation through IPA (PEIPA), takes place in cell differentiation, during which downregulation of PCF11 is coupled with upregulation of long genes with functions in cell morphology, adhesion, and migration. PEIPA targets distinct gene sets in different cell contexts with similar rules. Furthermore, PCF11 is autoregulated through a conserved IPA site, the removal of which leads to global activation of PASs close to gene promotors. Therefore, PCF11 uses distinct mechanisms to regulate genes of different sizes, and its autoregulation maintains homeostasis of PAS usage in the cell. : Wang et al. report a gene size-based dichotomic scheme by which the cleavage and polyadenylation factor PCF11 modulates gene expression. Distinct polyA site types are involved to regulate short and long genes. PCF11 expression level is autoregulated and is connected with long gene expression in cell differentiation and across tissues. Keywords: alternative polyadenylation, gene size, cell differentiation, intronic polyadenylation, autoregulation, 3ʹ, end processing, intron size