title: Poly(A) binding protein nuclear 1 levels affect alternative polyadenylation.
abstract: The choice for a polyadenylation site determines the length of the 3'-untranslated region (3'-UTRs) of an mRNA. Inclusion or exclusion of regulatory sequences in the 3'-UTR may ultimately affect gene expression levels. Poly(A) binding protein nuclear 1 (PABPN1) is involved in polyadenylation of pre-mRNAs. An alanine repeat expansion in PABPN1 (exp-PABPN1) causes oculopharyngeal muscular dystrophy (OPMD). We hypothesized that previously observed disturbed gene expression patterns in OPMD muscles may have been the result of an effect of PABPN1 on alternative polyadenylation, influencing mRNA stability, localization and translation. A single molecule polyadenylation site sequencing method was developed to explore polyadenylation site usage on a genome-wide level in mice overexpressing exp-PABPN1. We identified 2012 transcripts with altered polyadenylation site usage. In the far majority, more proximal alternative polyadenylation sites were used, resulting in shorter 3'-UTRs. 3'-UTR shortening was generally associated with increased expression. Similar changes in polyadenylation site usage were observed after knockdown or overexpression of expanded but not wild-type PABPN1 in cultured myogenic cells. Our data indicate that PABPN1 is important for polyadenylation site selection and that reduced availability of functional PABPN1 in OPMD muscles results in use of alternative polyadenylation sites, leading to large-scale deregulation of gene expression.
authors: Center for Human and Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors: Eleonora
authors: E
authors: de Klerk
authors: Andrea
authors: A
authors: Venema
authors: S Yahya
authors: SY
authors: Anvar
authors: Jelle J
authors: JJ
authors: Goeman
authors: Ouhua
authors: O
authors: Hu
authors: Capucine
authors: C
authors: Trollet
authors: George
authors: G
authors: Dickson
authors: Johan T
authors: JT
authors: den Dunnen
authors: Silvère M
authors: SM
authors: van der Maarel
authors: Vered
authors: V
authors: Raz
authors: Peter A C
authors: PA
authors: 't Hoen
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D002460:Cell Line; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D039122:Poly(A)-Binding Protein I / Q000378:metabolism*; D026723:Polyadenylation; D017423:Sequence Analysis, RNA
chemical_list: D020413:3' Untranslated Regions; C576588:PABPN1 protein, human; D039122:Poly(A)-Binding Protein I