Widespread allele-specific topological domains in the human genome are not confined to imprinted gene clusters.
Journal
Genome biology
ISSN: 1474-760X
Titre abrégé: Genome Biol
Pays: England
ID NLM: 100960660
Informations de publication
Date de publication:
03 03 2023
03 03 2023
Historique:
received:
18
05
2022
accepted:
13
02
2023
entrez:
3
3
2023
pubmed:
4
3
2023
medline:
8
3
2023
Statut:
epublish
Résumé
There is widespread interest in the three-dimensional chromatin conformation of the genome and its impact on gene expression. However, these studies frequently do not consider parent-of-origin differences, such as genomic imprinting, which result in monoallelic expression. In addition, genome-wide allele-specific chromatin conformation associations have not been extensively explored. There are few accessible bioinformatic workflows for investigating allelic conformation differences and these require pre-phased haplotypes which are not widely available. We developed a bioinformatic pipeline, "HiCFlow," that performs haplotype assembly and visualization of parental chromatin architecture. We benchmarked the pipeline using prototype haplotype phased Hi-C data from GM12878 cells at three disease-associated imprinted gene clusters. Using Region Capture Hi-C and Hi-C data from human cell lines (1-7HB2, IMR-90, and H1-hESCs), we can robustly identify the known stable allele-specific interactions at the IGF2-H19 locus. Other imprinted loci (DLK1 and SNRPN) are more variable and there is no "canonical imprinted 3D structure," but we could detect allele-specific differences in A/B compartmentalization. Genome-wide, when topologically associating domains (TADs) are unbiasedly ranked according to their allele-specific contact frequencies, a set of allele-specific TADs could be defined. These occur in genomic regions of high sequence variation. In addition to imprinted genes, allele-specific TADs are also enriched for allele-specific expressed genes. We find loci that have not previously been identified as allele-specific expressed genes such as the bitter taste receptors (TAS2Rs). This study highlights the widespread differences in chromatin conformation between heterozygous loci and provides a new framework for understanding allele-specific expressed genes.
Sections du résumé
BACKGROUND
There is widespread interest in the three-dimensional chromatin conformation of the genome and its impact on gene expression. However, these studies frequently do not consider parent-of-origin differences, such as genomic imprinting, which result in monoallelic expression. In addition, genome-wide allele-specific chromatin conformation associations have not been extensively explored. There are few accessible bioinformatic workflows for investigating allelic conformation differences and these require pre-phased haplotypes which are not widely available.
RESULTS
We developed a bioinformatic pipeline, "HiCFlow," that performs haplotype assembly and visualization of parental chromatin architecture. We benchmarked the pipeline using prototype haplotype phased Hi-C data from GM12878 cells at three disease-associated imprinted gene clusters. Using Region Capture Hi-C and Hi-C data from human cell lines (1-7HB2, IMR-90, and H1-hESCs), we can robustly identify the known stable allele-specific interactions at the IGF2-H19 locus. Other imprinted loci (DLK1 and SNRPN) are more variable and there is no "canonical imprinted 3D structure," but we could detect allele-specific differences in A/B compartmentalization. Genome-wide, when topologically associating domains (TADs) are unbiasedly ranked according to their allele-specific contact frequencies, a set of allele-specific TADs could be defined. These occur in genomic regions of high sequence variation. In addition to imprinted genes, allele-specific TADs are also enriched for allele-specific expressed genes. We find loci that have not previously been identified as allele-specific expressed genes such as the bitter taste receptors (TAS2Rs).
CONCLUSIONS
This study highlights the widespread differences in chromatin conformation between heterozygous loci and provides a new framework for understanding allele-specific expressed genes.
Identifiants
pubmed: 36869353
doi: 10.1186/s13059-023-02876-2
pii: 10.1186/s13059-023-02876-2
pmc: PMC9983196
doi:
Substances chimiques
Chromatin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
40Subventions
Organisme : Medical Research Council
ID : MR/T016787/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P000711/1
Pays : United Kingdom
Informations de copyright
© 2023. The Author(s).
Références
Nat Genet. 2016 May;48(5):481-7
pubmed: 27019110
Nat Methods. 2019 Dec;16(12):1297-1305
pubmed: 31740818
Epigenetics Chromatin. 2018 May 25;11(1):21
pubmed: 29801521
Genome Res. 2016 Jan;26(1):70-84
pubmed: 26518482
Genome Res. 2013 Oct;23(10):1624-35
pubmed: 23804403
Genome Res. 2017 May;27(5):801-812
pubmed: 27940952
Genome Biol. 2018 Dec 10;19(1):217
pubmed: 30526631
Science. 2015 Feb 27;347(6225):1017-21
pubmed: 25722416
Am J Hum Genet. 2017 Mar 2;100(3):444-453
pubmed: 28190458
Nat Biotechnol. 2010 Oct;28(10):1045-8
pubmed: 20944595
Nat Commun. 2018 Aug 7;9(1):3121
pubmed: 30087329
Front Genet. 2019 Jan 09;9:695
pubmed: 30687383
Nature. 2017 Sep 13;549(7671):219-226
pubmed: 28905911
Curr Opin Endocrinol Diabetes Obes. 2014 Feb;21(1):30-8
pubmed: 24322424
Nat Commun. 2018 Jan 15;9(1):189
pubmed: 29335486
Cell. 2014 Dec 18;159(7):1665-80
pubmed: 25497547
Clin Genet. 2017 Oct;92(4):415-422
pubmed: 28295210
Nucleic Acids Res. 2022 Jan 7;50(D1):D60-D71
pubmed: 34664666
Mol Cell. 2009 May 15;34(3):271-84
pubmed: 19450526
Nat Genet. 2019 May;51(5):835-843
pubmed: 31011212
Elife. 2020 May 12;9:
pubmed: 32396063
Nucleic Acids Res. 2013 May 1;41(10):5290-302
pubmed: 23585276
Proc Natl Acad Sci U S A. 2019 Sep 24;116(39):19431-19439
pubmed: 31506350
BMC Genet. 2019 Apr 30;20(1):43
pubmed: 31039743
Mol Cell. 2021 Apr 15;81(8):1682-1697.e7
pubmed: 33651988
Nature. 2015 Jul 9;523(7559):212-6
pubmed: 26030523
Nat Commun. 2020 Jul 9;11(1):3428
pubmed: 32647330
Proc Natl Acad Sci U S A. 2012 May 8;109(19):7403-8
pubmed: 22529396
Hum Mol Genet. 2020 Sep 30;29(R1):R107-R116
pubmed: 32592473
Genome Biol. 2023 Mar 3;24(1):40
pubmed: 36869353
Hum Mol Genet. 2010 Mar 1;19(5):901-19
pubmed: 20015958
PLoS Genet. 2014 Feb 13;10(2):e1004153
pubmed: 24550742
Bioinformatics. 2021 Jun 16;37(10):1339-1344
pubmed: 33196774
Bioinformatics. 2016 Feb 15;32(4):587-9
pubmed: 26508757
J Cell Biol. 2014 Jan 6;204(1):61-75
pubmed: 24395636
Proc Natl Acad Sci U S A. 2015 Nov 24;112(47):E6456-65
pubmed: 26499245
Genome Res. 2017 Nov;27(11):1939-1949
pubmed: 28855260
Bioinformatics. 2018 Aug 1;34(15):2538-2545
pubmed: 29579179
Genome Biol. 2020 Aug 3;21(1):193
pubmed: 32746892
Taiwan J Obstet Gynecol. 2012 Sep;51(3):342-9
pubmed: 23040914
Nature. 2014 Nov 20;515(7527):402-5
pubmed: 25409831
BMC Genomics. 2019 Jan 23;20(1):77
pubmed: 30674271
Genome Biol. 2019 Dec 12;20(1):272
pubmed: 31831055
Nucleic Acids Res. 2020 Dec 2;48(21):e123
pubmed: 33074315
Mol Cell. 2020 Apr 16;78(2):224-235.e5
pubmed: 32109364
Nat Commun. 2021 Jul 15;12(1):4338
pubmed: 34267199
Am J Hum Genet. 2013 Aug 8;93(2):224-35
pubmed: 23871723
J Cell Biol. 2002 May 13;157(4):579-89
pubmed: 11994314
Genome Res. 2017 Jan;27(1):157-164
pubmed: 27903644
Cell Mol Life Sci. 2013 Mar;70(5):795-814
pubmed: 22825660
Hum Mol Genet. 2008 Oct 1;17(19):3021-9
pubmed: 18617529
PLoS Genet. 2010 Jun 17;6(6):e1000992
pubmed: 20585555
Genome Res. 2014 Dec;24(12):2022-32
pubmed: 25236618
Nature. 2000 May 25;405(6785):482-5
pubmed: 10839546
Nat Protoc. 2021 Apr;16(4):2257-2285
pubmed: 33837305
BMC Genomics. 2021 Jul 3;22(1):499
pubmed: 34217222
Trends Biochem Sci. 2020 May;45(5):385-396
pubmed: 32311333
Nat Genet. 2015 Dec;47(12):1393-401
pubmed: 26502339
Nature. 2020 Feb;578(7793):129-136
pubmed: 32025019
J Med Genet. 2014 Aug;51(8):502-11
pubmed: 24996904
Genome Biol. 2018 Oct 4;19(1):151
pubmed: 30286773
Nat Rev Genet. 2019 Apr;20(4):235-248
pubmed: 30647469
Nature. 2015 Feb 19;518(7539):317-30
pubmed: 25693563
Cell. 2016 Nov 17;167(5):1369-1384.e19
pubmed: 27863249
Curr Opin Genet Dev. 2011 Apr;21(2):175-86
pubmed: 21342762
Bioessays. 2020 Oct;42(10):e1900249
pubmed: 32743818
PLoS Genet. 2006 Jun;2(6):e93
pubmed: 16789827
PLoS Comput Biol. 2013;9(3):e1002968
pubmed: 23526891
Genome Biol. 2019 Nov 28;20(1):255
pubmed: 31779666
Nature. 2009 Nov 19;462(7271):315-22
pubmed: 19829295
Nature. 2012 Sep 6;489(7414):57-74
pubmed: 22955616
Nature. 2012 Apr 11;485(7398):381-5
pubmed: 22495304
BMC Bioinformatics. 2018 Jul 31;19(1):279
pubmed: 30064362
J Hum Genet. 2013 Jul;58(7):402-9
pubmed: 23719190
Nat Rev Genet. 2015 Nov;16(11):653-64
pubmed: 26442639
Hum Mol Genet. 2007 Oct 15;16 Spec No. 2:R243-51
pubmed: 17911167
Nat Commun. 2020 Jan 7;11(1):54
pubmed: 31911579
Nucleic Acids Res. 2022 Jan 11;50(1):207-226
pubmed: 34931241
Curr Biol. 2000 May 18;10(10):607-10
pubmed: 10837224
Mol Cell Biol. 2007 Apr;27(7):2636-47
pubmed: 17242189
Genome Biol. 2012 Oct 03;13(10):R87
pubmed: 23034086
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
Genome Res. 2006 Mar;16(3):331-9
pubmed: 16467561
F1000Res. 2016 Jun 23;5:1479
pubmed: 27429743
Nat Methods. 2012 Feb 28;9(3):215-6
pubmed: 22373907
Genes (Basel). 2019 Dec 02;10(12):
pubmed: 31810366
Sci Transl Med. 2017 Jun 21;9(395):
pubmed: 28637928
Sci Rep. 2020 May 19;10(1):8275
pubmed: 32427849
Nature. 2011 Mar 3;471(7336):68-73
pubmed: 21289626
Mol Cell. 2008 Oct 10;32(1):129-39
pubmed: 18851839
Nucleic Acids Res. 2021 Jun 21;49(11):6315-6330
pubmed: 34107024
Cell. 2014 Oct 23;159(3):543-57
pubmed: 25417106
Bioinformatics. 2018 May 1;34(9):1568-1570
pubmed: 29244056
Sci Rep. 2019 Jun 27;9(1):9354
pubmed: 31249361
J Hum Genet. 2016 Feb;61(2):87-94
pubmed: 26377239
Nucleic Acids Res. 2019 Jan 8;47(D1):D766-D773
pubmed: 30357393
Hum Mol Genet. 2011 Apr 1;20(7):1363-74
pubmed: 21282187
Nucleic Acids Res. 2015 Jan;43(2):745-59
pubmed: 25539921
Genome Res. 2007 Dec;17(12):1731-42
pubmed: 17989250
F1000Res. 2018 Aug 24;7:1338
pubmed: 30254741
Science. 2012 Sep 7;337(6099):1190-5
pubmed: 22955828
Genome Biol. 2019 Dec 18;20(1):282
pubmed: 31847870
Mol Cell Biol. 2011 Aug;31(15):3094-104
pubmed: 21628529
Cell Syst. 2020 Feb 26;10(2):193-203.e4
pubmed: 32078798
Epigenetics Chromatin. 2011 Jan 31;4(1):1
pubmed: 21281512
Mamm Genome. 2009 Sep-Oct;20(9-10):699-710
pubmed: 19641963
Nat Methods. 2021 Sep;18(9):1046-1055
pubmed: 34480151
Hum Genet. 2017 Jan;136(1):39-54
pubmed: 27699474
Nature. 2000 May 25;405(6785):486-9
pubmed: 10839547
Cell. 2012 Nov 9;151(4):724-737
pubmed: 23141535
Nature. 2012 Apr 11;485(7398):376-80
pubmed: 22495300
Curr Protoc Bioinformatics. 2013;43:11.10.1-11.10.33
pubmed: 25431634
F1000Res. 2015 Nov 20;4:1310
pubmed: 26835000
PLoS Genet. 2012 Sep;8(9):e1002956
pubmed: 23028363
Genes (Basel). 2014 Aug 14;5(3):635-55
pubmed: 25257202
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Cell. 2015 Mar 12;160(6):1049-59
pubmed: 25768903
Am J Med Genet A. 2008 Aug 15;146A(16):2041-52
pubmed: 18627066
Cell Rep. 2021 Feb 9;34(6):108729
pubmed: 33567274
Genome Biol. 2015 Dec 01;16:259
pubmed: 26619908
Bioinformatics. 2021 Apr 20;37(3):422-423
pubmed: 32745185
Genome Res. 2012 Sep;22(9):1680-8
pubmed: 22955980
Hum Mol Genet. 2021 Jul 28;30(16):1509-1520
pubmed: 34132339
Nature. 2021 May;593(7858):238-243
pubmed: 33828297
PLoS Genet. 2009 Nov;5(11):e1000739
pubmed: 19956766
Bioinformatics. 2010 Mar 15;26(6):841-2
pubmed: 20110278
Genome Res. 2015 Jul;25(7):927-36
pubmed: 25953952
Curr Opin Cell Biol. 2013 Jun;25(3):327-33
pubmed: 23465542
Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10684-9
pubmed: 16815976
Hum Mol Genet. 2004 Oct 1;13 Spec No 2:R255-60
pubmed: 15358732
Cell Stem Cell. 2010 May 7;6(5):479-91
pubmed: 20452322