Heregulin-induced epigenetic regulation of the utrophin-A promoter.
Utrophin is the autosomal homolog of dystrophin, the product of the Duchenne's muscular dystrophy (DMD) locus. Utrophin is of therapeutic interest since its over-expression can compensate dystrophin's absence. Utrophin is enriched at neuromuscular junctions due to heregulin-mediated utrophin-A promoter activation. We demonstrate that heregulin activated MSK1/2 and phosphorylated histone H3 at serine 10 in cultured C2C12 muscle cells, in an ERK-dependent manner. MSK1/2 inhibition suppressed heregulin-mediated utrophin-A activation. MSK1 over-expression potentiated heregulin-mediated utrophin-A activation and chromatin remodeling at the utrophin-A promoter. These results identify MSK1/2 as key effectors modulating utrophin-A expression as well as identify novel targets for DMD therapy.
Basu
Utpal
U
Department of Physiology & Pennsylvania Muscle Institute, 3700 Hamilton Walk, University of Pennsylvania, Philadelphia, PA 19104-6085, USA.
Gyrd-Hansen
Mads
M
Baby
Santhosh M
SM
Lozynska
Olga
O
Krag
Thomas O B
TO
Jensen
Claus J
CJ
Frödin
Morten
M
Khurana
Tejvir S
TS
D000818:Animals; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects*; D006657:Histones / Q000378:metabolism; D051379:Mice; D008957:Models, Genetic; D032342:Muscle Cells / Q000187:drug effects / Q000201:enzymology; D020890:Neuregulin-1 / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D049411:Utrophin / Q000235:genetics* / Q000378:metabolism
D006657:Histones; D020890:Neuregulin-1; C483600:Utrn protein, mouse; D049411:Utrophin; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C485459:Rps6ka4 protein, mouse; C116919:mitogen and stress-activated protein kinase 1
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