Species-specific cis-regulatory elements in the 3′-untranslated region direct alternative polyadenylation of bone morphogenetic protein 2 mRNA

Donglin Liu, David T. Fritz, Melissa B. Rogers, Aaron J. Shatkin

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

BMP2 (bone morphogenetic protein 2) is a multifunctional member of the transforming growth factor-β family of growth factors. Disruption of BMP2 signaling results in developmental defects, cancers, and other diseases. BMP2 mRNAs are alternatively polyadenylated, resulting in mRNAs with distinct 3′-untranslated regions. The longer mRNA contains additional putative binding sites for post-transcriptional regulatory factors, including micro-RNAs. We combined functional assays with computational analyses of emerging genome data to define siteand species-specific polyadenylation determinants. In all mouse and human cell lines tested, shorter mRNAs resulting from using the first polyadenylation signal (PA1) were more abundant than mRNAs from the second signal (PA2). However, the PA1/PA2 usage ratios were 2-3-fold higher in human than in mouse cells. Expression of human BMP2 constructs in mouse cells and mouse constructs in human cells showed that cis-regulatory elements direct species-specific 3′ processing of BMP2 transcripts. A 72-nucleotide region downstream of PA2 in the mouse sequence contains two novel cis-acting elements previously hypothesized to regulate polyadenylation in a bioinformatics analysis. Mutations that humanized the mouse-specific elements lowered the affinity for cleavage stimulation factor CstF64 and significantly weakened the PA2 signal relative to the PA1 signal. Thus, we have experimentally defined for the first time cis-regulatory elements that control a species-specific difference in the 3′-end processing of BMP2 and potentially of other genes.

Original languageEnglish (US)
Pages (from-to)28010-28019
Number of pages10
JournalJournal of Biological Chemistry
Volume283
Issue number42
DOIs
StatePublished - Oct 17 2008

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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