Human FRG1 is an Actin-Bundling and a RNA-Associated Protein with Distinct Subcellular Localizations

Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) is critical for development of the vertebrate musculature and vasculature, however its precise molecular function is unknown. Because of its location 125 kb proximal to the FSHD1A lesion, a deletion in a subtelomeric macrosatellite DNA repeat array, it has been considered a candidate for mediating FSHD pathophysiology. This study investigates FRG1’s function to provide insight into FRG1’s role in vertebrate muscle development. First, we focus on the subcellular localization of FRG1 and identified FRG1 as a dynamic nuclear, cytoplamic, and sarcomeric protein. During myoblast differentiation, FRG1’s subcellular distribution changed dramatically with FRG1 eventually associating with the matured Z-discs. The Z-disc localization is confirmed in mouse myofibers, suggesting FRG1 may have a muscle-specific function involved in sarcomere maintenance or signaling. The nuclear fraction of the endogenous FRG1 is localized in nucleoli, Cajal bodies, and actively transcribed chromatin associated with nascent RNA transcripts, supporting a function in RNA biogenesis. Furthermore, we show that FRG1 interacts specifically with RNA in vitro, associates with mRNA in vivo, and directly interacts with the TAP mRNA export receptor. FRG1 also exists in a cytoplasmic pool that is dependent on an intact actin cytoskeleton for its localization and we demonstrate FRG1 itself is an actin binding protein. These data provide the first biochemical activities for human FRG1 and indicate that FRG1 dynamically shuttles between the nucleus and cytoplasm and is involved in aspects of RNA biogenesis, potentially including mRNA transport and localization.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Cell and Developmental Biology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2011

Author dc:creator

• Sun, Chia-Yun

Contributors dc:contributor

• Jones, Peter L.
• Bellini, Michel
• Brieher, William M.
• Ceman, Stephanie S.
• Nardulli, Ann M.

• FSHD region gene 1 (FRG1)
• RNA biogenesis
• mRNA transport
• Actin
• Z-disc
• Myogenesis
• Facioscapulohumeral muscular dystrophy (FSHD)
• Muscular dystrophy

Statement dc:rights

• Copyright 2010 Chia-Yun Sun

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/18617

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/18617