Linking aberrant chromatin features in chronic lymphocytic leukemia to transcription factor networks.
Aged
Amino Acid Motifs
Binding Sites
CCCTC-Binding Factor
/ genetics
Chromatin
/ chemistry
DNA
/ chemistry
DNA Methylation
Down-Regulation
Enhancer Elements, Genetic
Gene Expression Regulation, Leukemic
Gene Regulatory Networks
Histone Deacetylases
/ genetics
Histones
/ chemistry
Humans
Leukemia, Lymphocytic, Chronic, B-Cell
/ genetics
Middle Aged
Promoter Regions, Genetic
Protein Binding
Trans-Activators
/ genetics
DNA methylation
bivalent promoter
enhancer
gene regulatory networks
histone modifications
Journal
Molecular systems biology
ISSN: 1744-4292
Titre abrégé: Mol Syst Biol
Pays: England
ID NLM: 101235389
Informations de publication
Date de publication:
22 05 2019
22 05 2019
Historique:
entrez:
24
5
2019
pubmed:
24
5
2019
medline:
12
5
2020
Statut:
epublish
Résumé
In chronic lymphocytic leukemia (CLL), a diverse set of genetic mutations is embedded in a deregulated epigenetic landscape that drives cancerogenesis. To elucidate the role of aberrant chromatin features, we mapped DNA methylation, seven histone modifications, nucleosome positions, chromatin accessibility, binding of EBF1 and CTCF, as well as the transcriptome of B cells from CLL patients and healthy donors. A globally increased histone deacetylase activity was detected and half of the genome comprised transcriptionally downregulated partially DNA methylated domains demarcated by CTCF CLL samples displayed a H3K4me3 redistribution and nucleosome gain at promoters as well as changes of enhancer activity and enhancer linkage to target genes. A DNA binding motif analysis identified transcription factors that gained or lost binding in CLL at sites with aberrant chromatin features. These findings were integrated into a gene regulatory enhancer containing network enriched for B-cell receptor signaling pathway components. Our study predicts novel molecular links to targets of CLL therapies and provides a valuable resource for further studies on the epigenetic contribution to the disease.
Identifiants
pubmed: 31118277
doi: 10.15252/msb.20188339
pmc: PMC6529931
doi:
Substances chimiques
CCCTC-Binding Factor
0
CTCF protein, human
0
Chromatin
0
EBF1 protein, human
0
Histones
0
Trans-Activators
0
histone H3 trimethyl Lys4
0
DNA
9007-49-2
Histone Deacetylases
EC 3.5.1.98
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e8339Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
© 2019 The Authors. Published under the terms of the CC BY 4.0 license.
Références
Electrophoresis. 2004 Jun;25(10-11):1530-5
pubmed: 15188237
Genome Biol. 2009;10(3):R25
pubmed: 19261174
Nat Genet. 2015 Nov;47(11):1316-1325
pubmed: 26437030
Sci Adv. 2015 Jun 12;1(5):e1500447
pubmed: 26601204
PLoS Genet. 2017 Apr 18;13(4):e1006752
pubmed: 28419090
Nat Rev Cancer. 2011 Jul 07;11(8):588-96
pubmed: 21734722
Blood. 2005 Feb 15;105(4):1566-73
pubmed: 15471955
Bioinformatics. 2015 Jan 15;31(2):166-9
pubmed: 25260700
Blood. 2010 Feb 4;115(5):975-84
pubmed: 19965633
Nature. 2012 Aug 23;488(7412):504-7
pubmed: 22820252
Mol Cell Biol. 2008 Mar;28(6):2047-58
pubmed: 18212061
Nature. 2012 Sep 13;489(7415):309-12
pubmed: 22885698
Mol Syst Biol. 2019 Mar 4;15(3):e8584
pubmed: 30833303
Nature. 2014 Jun 26;510(7506):537-41
pubmed: 24847876
N Engl J Med. 2016 Jan 28;374(4):311-22
pubmed: 26639348
Bioinformatics. 2014 May 15;30(10):1363-9
pubmed: 24478339
Cell. 2017 Dec 14;171(7):1573-1588.e28
pubmed: 29224777
Nat Genet. 2015 Jul;47(7):746-56
pubmed: 26053498
Nature. 2012 Jan 04;481(7381):389-93
pubmed: 22217937
Cell. 2014 Dec 18;159(7):1665-80
pubmed: 25497547
Nat Commun. 2016 Jun 27;7:11938
pubmed: 27346425
N Engl J Med. 2015 Dec 17;373(25):2425-37
pubmed: 26639149
BMC Genomics. 2017 Feb 14;18(1):158
pubmed: 28196481
Bioinformatics. 2010 Mar 1;26(5):589-95
pubmed: 20080505
Cell Rep. 2017 Oct 17;21(3):784-797
pubmed: 29045844
Database (Oxford). 2015 Jul 07;2015:bav067
pubmed: 26153137
Nat Genet. 2012 Nov;44(11):1236-42
pubmed: 23064414
Biophys J. 2017 Feb 7;112(3):473-490
pubmed: 28131315
Cell. 2018 Apr 5;173(2):386-399.e12
pubmed: 29625054
Nat Genet. 2016 Aug;48(8):838-47
pubmed: 27322546
Nature. 2015 Jul 9;523(7559):212-6
pubmed: 26030523
Bioinformatics. 2014 Aug 1;30(15):2114-20
pubmed: 24695404
Genome Biol. 2014;15(12):550
pubmed: 25516281
Nat Rev Dis Primers. 2017 Jan 19;3:16096
pubmed: 28102226
EMBO J. 2010 Jul 7;29(13):2147-60
pubmed: 20517297
Cell. 2014 Dec 18;159(7):1538-48
pubmed: 25483776
Genome Biol. 2015 Aug 28;16:180
pubmed: 26316348
Am J Hematol. 2015 May;90(5):446-60
pubmed: 25908509
Nucleic Acids Res. 2001 Dec 15;29(24):4994-5000
pubmed: 11812829
BMC Genomics. 2014 Apr 15;15:284
pubmed: 24735413
Nature. 2015 Jul 23;523(7561):486-90
pubmed: 26083756
N Engl J Med. 2013 Jul 4;369(1):32-42
pubmed: 23782158
Leukemia. 2015 Mar;29(3):598-605
pubmed: 25151957
Mol Cancer. 2010 Oct 15;9:275
pubmed: 20950428
Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):6037-42
pubmed: 23530188
Nature. 2008 Jun 12;453(7197):948-51
pubmed: 18463634
Science. 2001 Aug 31;293(5535):1653-7
pubmed: 11533489
Genome Res. 2019 May;29(5):750-761
pubmed: 30948436
Oncotarget. 2016 Jan 19;7(3):2297-312
pubmed: 26506234
Bioinformatics. 2015 Aug 1;31(15):2560-4
pubmed: 25788621
Nature. 2015 Oct 22;526(7574):525-30
pubmed: 26466571
Trends Immunol. 2013 Dec;34(12):592-601
pubmed: 23928062
Genome Biol. 2010;11(12):R119
pubmed: 21143862
Genome Res. 2003 Nov;13(11):2498-504
pubmed: 14597658
Nat Genet. 2015 Oct;47(10):1149-57
pubmed: 26301496
Nat Struct Mol Biol. 2012 Nov;19(11):1185-92
pubmed: 23085715
Cell. 2013 Apr 11;153(2):307-19
pubmed: 23582322
Genes Dev. 2013 Jun 15;27(12):1318-38
pubmed: 23788621
Genome Biol. 2004;5(10):R80
pubmed: 15461798
Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13433-8
pubmed: 19666576
Blood. 2014 Jul 3;124(1):42-8
pubmed: 24868078
Nat Methods. 2017 Oct;14(10):975-978
pubmed: 28825706
Genome Biol. 2008;9(9):R137
pubmed: 18798982
Curr Opin Hematol. 2013 Jul;20(4):362-8
pubmed: 23719185
Bioinformatics. 2016 Jul 15;32(14):2233-5
pubmed: 27153652
Leukemia. 2013 Jan;27(1):150-8
pubmed: 22922567
Mol Cell. 2010 May 28;38(4):576-89
pubmed: 20513432
Nat Methods. 2012 Feb 28;9(3):215-6
pubmed: 22373907
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Nat Genet. 2011 Nov 27;44(1):40-6
pubmed: 22120008
Proc Natl Acad Sci U S A. 2006 May 16;103(20):7741-6
pubmed: 16684883
Nat Genet. 2016 Mar;48(3):253-64
pubmed: 26780610
Proc Natl Acad Sci U S A. 2017 Apr 4;114(14):E2911-E2919
pubmed: 28314854
Blood. 1992 Oct 15;80(8):2074-80
pubmed: 1382719
PLoS One. 2016 Dec 30;11(12):e0169159
pubmed: 28036404
Semin Cancer Biol. 2014 Feb;24:71-81
pubmed: 24018164
N Engl J Med. 2014 Mar 13;370(11):997-1007
pubmed: 24450857
Nat Rev Cancer. 2010 Jan;10(1):37-50
pubmed: 19956173
Nat Biotechnol. 2010 May;28(5):495-501
pubmed: 20436461
Mol Cell Biol. 2005 May;25(9):3575-82
pubmed: 15831463
Nucleic Acids Res. 2016 Jul 8;44(W1):W83-9
pubmed: 27098042
Trends Genet. 2018 Apr;34(4):257-269
pubmed: 29336845
Hematology Am Soc Hematol Educ Program. 2015;2015:368-77
pubmed: 26637745
Nucleic Acids Res. 2000 Jan 1;28(1):27-30
pubmed: 10592173
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Biomed Res Int. 2015;2015:347571
pubmed: 25789315
Genome Res. 2014 Aug;24(8):1285-95
pubmed: 24812327
Epigenetics. 2010 Nov-Dec;5(8):691-5
pubmed: 20716948
Nature. 2015 Oct 22;526(7574):519-24
pubmed: 26200345
Cell Rep. 2014 Aug 7;8(3):798-806
pubmed: 25066126
Genome Res. 2012 Feb;22(2):246-58
pubmed: 22156296
Cancer Cell. 2018 Dec 10;34(6):982-995.e7
pubmed: 30503705
Nat Med. 2018 Jun;24(6):868-880
pubmed: 29785028
Nucleic Acids Res. 2014 Apr;42(8):e69
pubmed: 24561809
Nat Genet. 2018 Jan;50(1):73-82
pubmed: 29255264
Blood. 2009 Sep 3;114(10):2044-50
pubmed: 19553638
Nat Rev Cancer. 2009 Jun;9(6):400-14
pubmed: 19440234