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Author Notes:

To whom correspondence should be addressed. Tel: +1 404 727 4546; Email: acorbe2@emory.edu.

Correspondence may also be addressed to Grace K. Pavlath. Email: gpavlat@emory.edu

Conflict of interest statement: None declared.

Subjects:

Research Funding:

National Institutes of Health (NIH) [5R01AR061987 to G.K.P., A.H.C., 5F31AR069994 to B.L.P.]; Muscular Dystrophy Association [422006 to A.H.C.]; Canadian Institute for Health Research Operating Grant [MOP-142399 to I.E.G.].

Funding for open access charge: NIH [2R01AR061987].

This work was supported in part by the Emory Integrated Genomics Core (EIGC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • OCULOPHARYNGEAL MUSCULAR-DYSTROPHY
  • AU-RICH ELEMENTS
  • PRE-MESSENGER-RNA
  • NUCLEAR POLY(A)-BINDING PROTEIN
  • MUSCLE-CELL DIFFERENTIATION
  • ANTIGEN R HUR
  • ALTERNATIVE POLYADENYLATION
  • P53 TRANSLATION
  • EXPRESSION
  • STABILITY

Post-transcriptional regulation of Pabpn1 by the RNA binding protein HuR

Journal Title:

Nucleic Acids Research

Volume:

Volume 46, Number 15

Publisher:

, Pages 7643-7661

Type of Work:

Article | Final Publisher PDF

Abstract:

RNA processing is critical for proper spatial and temporal control of gene expression. The ubiquitous nuclear polyadenosine RNA binding protein, PABPN1, post-transcriptionally regulates multiple steps of gene expression. Mutations in the PABPN1 gene expanding an N-terminal alanine tract in the PABPN1 protein from 10 alanines to 11-18 alanines cause the muscle-specific disease oculopharyngeal muscular dystrophy (OPMD), which affects eyelid, pharynx, and proximal limb muscles. Previous work revealed that the Pabpn1 transcript is unstable, contributing to low steady-state Pabpn1 mRNA and protein levels in vivo, specifically in skeletal muscle, with even lower levels in muscles affected in OPMD. Thus, low levels of PABPN1 protein could predispose specific tissues to pathology in OPMD. However, no studies have defined the mechanisms that regulate Pabpn1 expression. Here, we define multiple cis-regulatory elements and a trans-acting factor, HuR, which regulate Pabpn1 expression specifically in mature muscle in vitro and in vivo. We exploit multiple models including C2C12 myotubes, primary muscle cells, and mice to determine that HuR decreases Pabpn1 expression. Overall, we have uncovered a mechanism in mature muscle that negatively regulates Pabpn1 expression in vitro and in vivo, which could provide insight to future studies investigating therapeutic strategies for OPMD treatment.

Copyright information:

© The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/).

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