title: Telomere position effect regulates DUX4 in human facioscapulohumeral muscular dystrophy.
abstract: Telomeres may regulate human disease by at least two independent mechanisms. First, replicative senescence occurs once short telomeres generate DNA-damage signals that produce a barrier to tumor progression. Second, telomere position effects (TPE) could change gene expression at intermediate telomere lengths in cultured human cells. Here we report that telomere length may contribute to the pathogenesis of facioscapulohumeral muscular dystrophy (FSHD). FSHD is a late-onset disease genetically residing only 25-60 kilobases from the end of chromosome 4q. We used a floxable telomerase to generate isogenic clones with different telomere lengths from affected patients and their unaffected siblings. DUX4, the primary candidate for FSHD pathogenesis, is upregulated over ten-fold in FSHD myoblasts and myotubes with short telomeres, and its expression is inversely proportional to telomere length. FSHD may be the first known human disease in which TPE contributes to age-related phenotype.
authors: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Guido
authors: G
authors: Stadler
authors: Fedik
authors: F
authors: Rahimov
authors: Oliver D
authors: OD
authors: King
authors: Jennifer C J
authors: JC
authors: Chen
authors: Jerome D
authors: JD
authors: Robin
authors: Kathryn R
authors: KR
authors: Wagner
authors: Jerry W
authors: JW
authors: Shay
authors: Charles P
authors: CP
authors: Emerson
authors: Woodring E
authors: WE
authors: Wright
mesh_terms: D002478:Cells, Cultured; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics* / Q000473:pathology; D032446:Myoblasts / Q000502:physiology; D016615:Telomere / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins
references: Gene. 1999 Aug 5;236(1):25-32
references: 10433963
references: Adv Genet. 2008;61:1-43
references: 18282501
references: EMBO Rep. 2002 Nov;3(11):1055-61
references: 12393752
references: Am J Hum Genet. 2012 Apr 6;90(4):628-35
references: 22482803
references: Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18157-62
references: 17984056
references: Semin Cancer Biol. 2011 Dec;21(6):349-53
references: 22015685
references: Mol Cell Biol. 2006 Mar;26(5):1865-78
references: 16479005
references: Eur J Hum Genet. 2012 Apr;20(4):404-10
references: 22108603
references: Neuromuscul Disord. 2007 Aug;17(8):611-23
references: 17588759
references: Hypertension. 2000 Aug;36(2):195-200
references: 10948077
references: Hum Mol Genet. 1994 Aug;3(8):1287-95
references: 7987304
references: EMBO J. 2008 Oct 22;27(20):2766-79
references: 18833193
references: Aging Cell. 2004 Jun;3(3):97-102
references: 15153177
references: Nat Genet. 1992 Sep;2(1):26-30
references: 1363881
references: J Cell Mol Med. 2013 Jan;17(1):76-89
references: 23206257
references: Curr Protoc Cell Biol. 2003 Nov;Chapter 18:Unit 18.6
references: 18228424
references: Hum Mol Genet. 2012 Oct 15;21(20):4419-30
references: 22798623
references: Neuromuscul Disord. 2001 Sep;11(6-7):525-9
references: 11525880
references: Genes Dev. 1993 Jul;7(7A):1133-45
references: 8319906
references: Cell. 1990 Nov 16;63(4):751-62
references: 2225075
references: Science. 2010 Sep 24;329(5999):1650-3
references: 20724583
references: Trends Mol Med. 2011 May;17(5):252-8
references: 21288772
references: Stem Cells. 2007 Dec;25(12):3085-92
references: 17823235
references: J Med Genet. 2004 Nov;41(11):826-36
references: 15520407
references: Dev Cell. 2012 Jan 17;22(1):38-51
references: 22209328
references: Hum Mol Genet. 2006 Jul 1;15(13):2125-37
references: 16717057
references: Aging Cell. 2007 Aug;6(4):515-23
references: 17559502
references: Hum Gene Ther. 1997 Aug 10;8(12):1429-38
references: 9287143
references: Nucleus. 2010 Jan-Feb;1(1):30-6
references: 21327102
references: Science. 2001 Jun 15;292(5524):2075-7
references: 11408657
references: Hum Mol Genet. 1993 Dec;2(12):2037-42
references: 8111371
references: Genetics. 1943 Nov;28(6):491-511
references: 17247100
references: Nucleic Acids Res. 2001 Aug 1;29(15):3164-71
references: 11470873
references: Clin Genet. 2009 Jun;75(6):550-5
references: 19320656
references: Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14602-7
references: 9405659
references: Nat Rev Genet. 2007 Apr;8(4):272-85
references: 17363976
references: Aging (Albany NY). 2009 Jul 17;1(7):608-21
references: 20157543
references: Muscle Nerve Suppl. 1995;(2):S81-4
references: 23573591
references: Phys Ther. 2008 Jan;88(1):105-13
references: 17986494
references: Cell. 1984 Feb;36(2):469-81
references: 6319027
references: Oncogene. 2003 Jan 23;22(3):433-44
references: 12545164
references: PLoS Genet. 2009 Feb;5(2):e1000394
references: 19247430
references: Eur J Hum Genet. 2009 Dec;17(12):1615-24
references: 19809486
references: PLoS Genet. 2010 Oct 28;6(10):e1001181
references: 21060811
references: Cell. 2002 Aug 9;110(3):339-48
references: 12176321
references: Skelet Muscle. 2011 Mar 08;1(1):12
references: 21798090