TY - JOUR
T1 - Conserved proximal promoter elements control repulsive guidance molecule c/hemojuvelin (Hfe2) gene transcription in skeletal muscle
AU - Severyn, Christopher J.
AU - Rotwein, Peter
N1 - Funding Information:
We thank Lisa Wilson and David Kuninger for assistance with preliminary experiments, Dr. Melissa Wong of OHSU for mouse tissues, and other members of our laboratory for helpful comments during the development of this work. These studies have been supported in part by National Institutes of Health grants T32 HL007781 (Training Grant in Molecular Hematology) and F30 HL095327 (to C. J. S.), and by R01 DK042748-21 (to P. R.).
PY - 2010/12
Y1 - 2010/12
N2 - Repulsive guidance molecule c (RGMc; gene symbol: Hfe2) plays a critical role in iron metabolism. Inactivating mutations cause juvenile hemochromatosis, a severe iron overload disorder. Understanding mechanisms controlling RGMc biosynthesis has been hampered by minimal information about the RGMc gene. Here we define the structure, examine the evolution, and establish mechanisms of regulation of the mouse RGMc gene. RGMc is a 4-exon gene that undergoes alternative RNA splicing to yield 3 mRNAs with 5' different untranslated regions. Gene transcription is induced during myoblast differentiation, producing all 3 mRNAs. We identify 3 critical promoter elements responsible for transcriptional activation in skeletal muscle, comprising paired E-boxes, a putative Stat and/or Ets element, and a MEF2 site, and muscle transcription factors myogenin and MEF2C stimulate RGMc promoter function in non-muscle cells. As these elements are conserved in RGMc genes from multiple species, our results suggest that RGMc has been a muscle-enriched gene throughout its evolutionary history.
AB - Repulsive guidance molecule c (RGMc; gene symbol: Hfe2) plays a critical role in iron metabolism. Inactivating mutations cause juvenile hemochromatosis, a severe iron overload disorder. Understanding mechanisms controlling RGMc biosynthesis has been hampered by minimal information about the RGMc gene. Here we define the structure, examine the evolution, and establish mechanisms of regulation of the mouse RGMc gene. RGMc is a 4-exon gene that undergoes alternative RNA splicing to yield 3 mRNAs with 5' different untranslated regions. Gene transcription is induced during myoblast differentiation, producing all 3 mRNAs. We identify 3 critical promoter elements responsible for transcriptional activation in skeletal muscle, comprising paired E-boxes, a putative Stat and/or Ets element, and a MEF2 site, and muscle transcription factors myogenin and MEF2C stimulate RGMc promoter function in non-muscle cells. As these elements are conserved in RGMc genes from multiple species, our results suggest that RGMc has been a muscle-enriched gene throughout its evolutionary history.
KW - Hemojuvelin
KW - Juvenile hemochromatosis
KW - Molecular evolution
KW - RGMc
KW - Repulsive guidance molecule (RGM)
KW - Transcriptional regulation
UR - http://www.scopus.com/inward/record.url?scp=78449299628&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78449299628&partnerID=8YFLogxK
U2 - 10.1016/j.ygeno.2010.09.001
DO - 10.1016/j.ygeno.2010.09.001
M3 - Article
C2 - 20858542
AN - SCOPUS:78449299628
SN - 0888-7543
VL - 96
SP - 342
EP - 351
JO - Genomics
JF - Genomics
IS - 6
ER -