title: Chromatin remodeling of human subtelomeres and TERRA promoters upon cellular senescence: commonalities and differences between chromosomes.
abstract: Subtelomeres are patchworks of evolutionary conserved sequence blocks and harbor the transcriptional start sites for telomere repeat containing RNAs (TERRA). Recent studies suggest that the interplay between telomeres and subtelomeric chromatin is required for maintaining telomere function. To further characterize chromatin remodeling of subtelomeres in relation to telomere shortening and cellular senescence, we systematically quantified histone modifications and DNA methylation at the subtelomeres of chromosomes 7q and 11q in primary human WI-38 fibroblasts. Upon senescence, both subtelomeres were characterized by a decrease in markers of constitutive heterochromatin, suggesting relative chromatin relaxation. However, we did not find increased levels of markers of euchromatin or derepression of the 7q VIPR2 gene. The repressed state of the subtelomeres was maintained upon senescence, which could be attributed to a rise in levels of facultative heterochromatin markers at both subtelomeres. While senescence-induced subtelomeric chromatin remodeling was similar for both chromosomes, chromatin remodeling at TERRA promoters displayed chromosome-specific patterns. At the 7q TERRA promoter, chromatin structure was co-regulated with the more proximal subtelomere. In contrast, the 11q TERRA promoter, which was previously shown to be bound by CCCTC-binding factor CTCF, displayed lower levels of markers of constitutive heterochromatin that did not change upon senescence, whereas levels of markers of facultative heterochromatin decreased upon senescence. In line with the chromatin state data, transcription of 11q TERRA but not 7q TERRA was detected. Our study provides a detailed description of human subtelomeric chromatin dynamics and shows distinct regulation of the TERRA promoters of 7q and 11q upon cellular senescence.
authors: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Peter E
authors: PE
authors: Thijssen
authors: Elmar W
authors: EW
authors: Tobi
authors: Judit
authors: J
authors: Balog
authors: Suzanne G
authors: SG
authors: Schouten
authors: Dennis
authors: D
authors: Kremer
authors: Fatiha
authors: F
authors: El Bouazzaoui
authors: Peter
authors: P
authors: Henneman
authors: Hein
authors: H
authors: Putter
authors: P
authors: P
authors: Eline Slagboom
authors: Bastiaan T
authors: BT
authors: Heijmans
authors: Silvère M
authors: SM
authors: van der Maarel
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D002877:Chromosomes, Human / Q000235:genetics*; D022041:Euchromatin / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006570:Heterochromatin / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012313:RNA / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D016615:Telomere / Q000235:genetics*; D059506:Telomere Shortening; D014158:Transcription, Genetic
chemical_list: D015415:Biomarkers; D022041:Euchromatin; D006570:Heterochromatin; D006657:Histones; D012313:RNA; D008239:Lysine
keywords: TERRA transcripts; cellular aging; chromatin remodeling; histone modifications; senescence; subtelomere
references: Nat Protoc. 2006;1(1):179-85
references: 17406230
references: J Gerontol A Biol Sci Med Sci. 2009 Apr;64(4):426-34
references: 19223605
references: Aging Cell. 2012 Feb;11(1):24-8
references: 21981348
references: RNA. 2009 Dec;15(12):2186-94
references: 19850908
references: Nat Struct Mol Biol. 2010 Oct;17(10):1218-25
references: 20890289
references: Nat Genet. 2007 Feb;39(2):243-50
references: 17237781
references: Aging Dis. 2012 Apr;3(2):164-70
references: 22724077
references: JAMA. 2011 Jul 6;306(1):42-4
references: 21730239
references: Aging Cell. 2006 Aug;5(4):325-30
references: 16913878
references: Physiol Rev. 2008 Apr;88(2):557-79
references: 18391173
references: Nat Struct Mol Biol. 2012 Sep;19(9):948-56
references: 22922742
references: Nature. 1990 May 31;345(6274):458-60
references: 2342578
references: Transl Res. 2010 Apr;155(4):166-9
references: 20303464
references: Cell. 2005 Nov 18;123(4):581-92
references: 16286007
references: Nucleic Acids Res. 2007 Jul;35(Web Server issue):W71-4
references: 17485472
references: Eur J Hum Genet. 2012 Feb;20(2):185-91
references: 21811308
references: Nat Genet. 2003 Feb;33(2):203-7
references: 12539050
references: J Neurogenet. 2012 Jun;26(2):245-51
references: 22364520
references: Epigenetics. 2012 Jun 1;7(6):579-84
references: 22522912
references: PLoS Genet. 2012;8(6):e1002747
references: 22719262
references: EMBO J. 2012 Nov 5;31(21):4165-78
references: 23010778
references: Nucleic Acids Res. 2002 May 15;30(10):e47
references: 12000852
references: Curr Biol. 1998 Feb 26;8(5):279-82
references: 9501072
references: Mol Cell Biol. 2009 Aug;29(16):4519-26
references: 19528237
references: Nucleic Acids Res. 2012 Aug;40(14):6649-59
references: 22553368
references: Nat Rev Genet. 2007 Apr;8(4):299-309
references: 17363977
references: Exp Cell Res. 1965 Mar;37:614-36
references: 14315085
references: Genome Res. 2011 Sep;21(9):1426-37
references: 21803857
references: PLoS One. 2012;7(5):e37933
references: 22666415
references: Genome Biol. 2007;8(7):R151
references: 17663781
references: Annu Rev Genet. 2008;42:301-34
references: 18680434
references: Nat Genet. 2003 Dec;35(4):315-7
references: 14634647
references: Circ Res. 2012 Jun 22;111(1):97-109
references: 22723221
references: Mol Cell. 2005 Dec 22;20(6):971-8
references: 16364921
references: Nature. 2009 Jun 11;459(7248):802-7
references: 19516333
references: Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12325-30
references: 21746928
references: Mol Cell. 2012 Jul 27;47(2):203-14
references: 22795131
references: Am J Epidemiol. 2007 Jan 1;165(1):14-21
references: 17043079
references: J Cell Sci. 2008 Dec 15;121(Pt 24):4018-28
references: 19056671
references: Science. 2007 Nov 2;318(5851):798-801
references: 17916692
references: J Cell Biol. 1996 Nov;135(4):867-81
references: 8922373
references: PLoS Genet. 2009 Jul;5(7):e1000559
references: 19593370
references: Nature. 2005 Sep 1;437(7055):94-100
references: 16136133
references: Cell. 2005 Nov 18;123(4):593-605
references: 16286008
references: Exp Gerontol. 1996 Jan-Apr;31(1-2):235-43
references: 8706793