TNF inhibits Notch-1 in skeletal muscle cells by Ezh2 and DNA methylation mediated repression: implications in duchenne muscular dystrophy.
BACKGROUND
Classical NF-kappaB signaling functions as a negative regulator of skeletal myogenesis through potentially multiple mechanisms. The inhibitory actions of TNFalpha on skeletal muscle differentiation are mediated in part through sustained NF-kappaB activity. In dystrophic muscles, NF-kappaB activity is compartmentalized to myofibers to inhibit regeneration by limiting the number of myogenic progenitor cells. This regulation coincides with elevated levels of muscle derived TNFalpha that is also under IKKbeta and NF-kappaB control.


RESULTS
Based on these findings we speculated that in DMD, TNFalpha secreted from myotubes inhibits regeneration by directly acting on satellite cells. Analysis of several satellite cell regulators revealed that TNFalpha is capable of inhibiting Notch-1 in satellite cells and C2C12 myoblasts, which was also found to be dependent on NF-kappaB. Notch-1 inhibition occurred at the mRNA level suggesting a transcriptional repression mechanism. Unlike its classical mode of action, TNFalpha stimulated the recruitment of Ezh2 and Dnmt-3b to coordinate histone and DNA methylation, respectively. Dnmt-3b recruitment was dependent on Ezh2.


CONCLUSIONS
We propose that in dystrophic muscles, elevated levels of TNFalpha and NF-kappaB inhibit the regenerative potential of satellite cells via epigenetic silencing of the Notch-1 gene.
Acharyya
Swarnali
S
Human Cancer Genetics and Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, United States of America.
Sharma
Sudarshana M
SM
Cheng
Alfred S
AS
Ladner
Katherine J
KJ
He
Wei
W
Kline
William
W
Wang
Huating
H
Ostrowski
Michael C
MC
Huang
Tim H
TH
Guttridge
Denis C
DC
D000818:Animals; D019175:DNA Methylation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects*; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D063151:Polycomb Repressive Complex 2; D011401:Promoter Regions, Genetic / Q000235:genetics; D051881:Receptor, Notch1 / Q000172:deficiency / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016328:NF-kappa B; D051881:Receptor, Notch1; D014409:Tumor Necrosis Factor-alpha; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2
Cell Cycle. 2007 May 2;6(9):1040-3
17457052
Mol Cell Biol. 2007 Jun;27(12):4374-87
17438126
Mol Cell. 2004 Mar 26;13(6):853-65
15053878
Curr Opin Pharmacol. 2007 Jun;7(3):303-9
17475556
Curr Opin Rheumatol. 2005 Nov;17(6):707-13
16224247
Nat Rev Genet. 2007 Jan;8(1):9-22
17173055
Science. 2000 Sep 1;289(5484):1550-4
10968790
Nucl Recept Signal. 2005;3:e003
16604171
Mol Ther. 2007 May;15(5):867-77
17387336
Nat Genet. 2008 Jun;40(6):741-50
18488029
Nat Genet. 2004 Dec;36(12):1296-300
15516932
J Mol Med (Berl). 2008 Jul;86(7):747-59
18246321
Neuromuscul Disord. 2008 Mar;18(3):227-38
18207402
Genesis. 2000 Feb;26(2):165-6
10686620
Cancer Res. 2000 Feb 1;60(3):588-94
10676641
Cell. 2004 Aug 6;118(3):285-96
15294155
Rejuvenation Res. 2004 Spring;7(1):9-11
15256040
Mol Cell. 2001 Sep;8(3):719-25
11583633
Science. 2000 Sep 29;289(5488):2363-6
11009425
J Biol Chem. 2003 Jan 24;278(4):2294-303
12431991
Cancer Res. 2008 Mar 15;68(6):1786-96
18339859
Sci STKE. 2005 May 17;2005(284):re6
15900032
Mol Cell Biol. 2007 Jun;27(11):4018-27
17403896
Mol Cell Biol. 1999 Sep;19(9):5923-9
10454539
Cell Cycle. 2007 Jun 15;6(12):1451-4
17581278
Genesis. 2005 Nov;43(3):120-8
16158413
Trends Mol Med. 2007 Dec;13(12):520-6
17983835
Science. 2002 Nov 1;298(5595):1039-43
12351676
FASEB J. 2004 Apr;18(6):676-82
15054089
Clin Exp Pharmacol Physiol. 2008 Jul;35(7):846-51
18215180
J Biol Chem. 2006 Aug 25;281(34):24790-802
16766534
Genes Dev. 2004 Nov 1;18(21):2627-38
15520282
Genes Dev. 2006 Jun 1;20(11):1405-28
16751179
Dev Cell. 2002 Sep;3(3):397-409
12361602
J Clin Invest. 2006 Nov;116(11):2945-54
17080195
Trends Mol Med. 2008 Feb;14(2):82-91
18218339
Curr Opin Clin Nutr Metab Care. 2004 Jul;7(4):443-50
15192448
Nature. 2006 Feb 16;439(7078):871-4
16357870
FASEB J. 2001 May;15(7):1169-80
11344085
Am J Physiol Cell Physiol. 2007 May;292(5):C1660-71
17151142
Mol Cell Biol. 1999 Aug;19(8):5785-99
10409765
Am J Physiol Regul Integr Comp Physiol. 2005 Feb;288(2):R345-53
15637171
Eur Cytokine Netw. 2000 Dec;11(4):552-9
11125297
Nature. 2008 Nov 27;456(7221):502-6
18806774
Nat Rev Drug Discov. 2003 May;2(5):379-90
12750741
Mol Cell Biol. 2006 Aug;26(15):5771-83
16847330
J Nutr Biochem. 2006 Aug;17(8):501-8
16517142
Mol Cell Biol. 2009 Oct;29(20):5488-504
19687301
J Clin Invest. 2007 Apr;117(4):889-901
17380205
Cell. 1987 Aug 14;50(4):555-63
3607879
Hum Mol Genet. 2002 Feb 1;11(3):263-72
11823445
J Cell Biol. 2008 Feb 25;180(4):787-802
18299349
Sci STKE. 2006 Oct 17;2006(357):re13
17047224
Cell. 2007 Jun 1;129(5):999-1010
17540178
Development. 2007 Nov;134(22):3953-7
17965049
Oncogene. 2003 Sep 29;22(42):6598-608
14528285
Am J Physiol. 1999 Aug;277(2):C320-9
10444409
Genes Dev. 2004 Jul 1;18(13):1592-605
15231737
Nat Rev Mol Cell Biol. 2006 Oct;7(10):762-73
16971897
Cancer Lett. 2003 Feb 20;190(2):125-33
12565166
Cell. 2008 Feb 8;132(3):344-62
18267068
Nat Rev Mol Cell Biol. 2007 Jan;8(1):49-62
17183360