Stratifying TAD boundaries pinpoints focal genomic regions of regulation, damage, and repair.

Publisher: Oxford University Press Country of Publication: England NLM ID: 100912837 Publication Model: Print Cited Medium: Internet ISSN: 1477-4054 (Electronic) Linking ISSN: 14675463 NLM ISO Abbreviation: Brief Bioinform Subsets: MEDLINE

Publication: Oxford : Oxford University Press
Original Publication: London ; Birmingham, AL : H. Stewart Publications, [2000-

DNA Repair* ; DNA Breaks, Double-Stranded* ; Chromatin*/metabolism ; Chromatin*/genetics ; Gene Expression Regulation*; Humans ; Transcription Factors/metabolism ; Transcription Factors/genetics ; Animals ; Genomics/methods ; Genomic Instability ; Chromatin Assembly and Disassembly

Advances in chromatin mapping have exposed the complex chromatin hierarchical organization in mammals, including topologically associating domains (TADs) and their substructures, yet the functional implications of this hierarchy in gene regulation and disease progression are not fully elucidated. Our study delves into the phenomenon of shared TAD boundaries, which are pivotal in maintaining the hierarchical chromatin structure and regulating gene activity. By integrating high-resolution Hi-C data, chromatin accessibility, and DNA double-strand breaks (DSBs) data from various cell lines, we systematically explore the complex regulatory landscape at high-level TAD boundaries. Our findings indicate that these boundaries are not only key architectural elements but also vibrant hubs, enriched with functionally crucial genes and complex transcription factor binding site-clustered regions. Moreover, they exhibit a pronounced enrichment of DSBs, suggesting a nuanced interplay between transcriptional regulation and genomic stability. Our research provides novel insights into the intricate relationship between the 3D genome structure, gene regulation, and DNA repair mechanisms, highlighting the role of shared TAD boundaries in maintaining genomic integrity and resilience against perturbations. The implications of our findings extend to understanding the complexities of genomic diseases and open new avenues for therapeutic interventions targeting the structural and functional integrity of TAD boundaries.
(© The Author(s) 2024. Published by Oxford University Press.)

Science. 2015 Nov 27;350(6264):1096-101. (PMID: 26472758)
Cell. 2018 Sep 20;175(1):224-238.e15. (PMID: 30173918)
Nat Commun. 2020 Dec 2;11(1):6178. (PMID: 33268790)
Nucleic Acids Res. 2016 Apr 20;44(7):e70. (PMID: 26704975)
Nucleic Acids Res. 2018 Jan 4;46(D1):D252-D259. (PMID: 29140464)
Nature. 2012 Apr 11;485(7398):376-80. (PMID: 22495300)
Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):12027-32. (PMID: 16880385)
Bioinformatics. 2012 Nov 1;28(21):2843-4. (PMID: 22923296)
Science. 2009 Oct 9;326(5950):289-93. (PMID: 19815776)
Nat Methods. 2017 Jul;14(7):679-685. (PMID: 28604721)
Genome Biol. 2018 Dec 10;19(1):217. (PMID: 30526631)
Mol Cell. 2012 Dec 14;48(5):723-33. (PMID: 23122415)
DNA Repair (Amst). 2014 Oct;22:165-74. (PMID: 25087188)
Mol Cell. 2019 Jul 25;75(2):267-283.e12. (PMID: 31202576)
Proc Natl Acad Sci U S A. 2009 May 5;106(18):7273-80. (PMID: 19351897)
Carcinogenesis. 2010 Jun;31(6):961-7. (PMID: 20400477)
Nucleic Acids Res. 2016 Jul 8;44(W1):W160-5. (PMID: 27079975)
Bioinformatics. 2011 Apr 1;27(7):1017-8. (PMID: 21330290)
Brief Bioinform. 2020 Jul 15;21(4):1397-1410. (PMID: 31504171)
Nat Rev Genet. 2009 Jul;10(7):457-66. (PMID: 19506577)
Gene. 2018 Aug 15;667:83-94. (PMID: 29772251)
Nature. 2014 Mar 27;507(7493):455-461. (PMID: 24670763)
Trends Genet. 2023 Jan;39(1):1-4. (PMID: 35934594)
Nat Protoc. 2009;4(1):44-57. (PMID: 19131956)
Genes Dev. 2016 Jun 15;30(12):1357-82. (PMID: 27340173)
Nat Methods. 2014 Jan;11(1):73-78. (PMID: 24317252)
Cell. 2014 Dec 18;159(7):1665-80. (PMID: 25497547)
Mol Cell. 2004 Dec 22;16(6):979-90. (PMID: 15610740)
Nat Commun. 2023 Dec 7;14(1):8111. (PMID: 38062027)
Cell. 2005 Sep 23;122(6):947-56. (PMID: 16153702)
DNA Repair (Amst). 2021 Dec;108:103232. (PMID: 34678589)
Cell. 2017 Jul 27;170(3):507-521.e18. (PMID: 28735753)
Mol Cell. 2019 Jul 25;75(2):252-266.e8. (PMID: 31202577)
Cell Rep. 2019 Oct 15;29(3):560-572.e4. (PMID: 31618627)
Cell. 2020 Sep 17;182(6):1474-1489.e23. (PMID: 32841603)
Genes (Basel). 2021 Aug 10;12(8):. (PMID: 34440403)
Genome Res. 2017 Mar;27(3):479-490. (PMID: 28057745)
Nat Commun. 2018 Feb 7;9(1):542. (PMID: 29416042)
Cell. 2013 Aug 15;154(4):801-13. (PMID: 23953112)
Nucleic Acids Res. 2021 Jan 8;49(D1):D947-D955. (PMID: 32663312)
Nat Rev Genet. 2024 Feb;25(2):123-141. (PMID: 37673975)
Cell. 2014 Sep 11;158(6):1431-1443. (PMID: 25215497)
Am J Hum Genet. 2021 Feb 4;108(2):269-283. (PMID: 33545030)
Nature. 2012 Sep 6;489(7414):57-74. (PMID: 22955616)
Trends Genet. 2016 Apr;32(4):225-237. (PMID: 26862051)
Mol Cell Proteomics. 2023 Feb;22(2):100496. (PMID: 36640924)
Proc Natl Acad Sci U S A. 2021 Jan 19;118(3):. (PMID: 33408251)
Bioinformatics. 2015 Jul 15;31(14):2382-3. (PMID: 25765347)
Cell. 2013 Mar 14;152(6):1344-54. (PMID: 23498941)
Nature. 2015 Jul 9;523(7559):240-4. (PMID: 26030525)
Sci Rep. 2015 Feb 16;5:8465. (PMID: 25682954)
Science. 2009 Jun 26;324(5935):1720-3. (PMID: 19443739)
Nat Genet. 2020 Jan;52(1):8-16. (PMID: 31925403)
BMC Evol Biol. 2010 Oct 20;10:316. (PMID: 20961448)
Nature. 2021 Feb;590(7847):660-665. (PMID: 33597753)
Cell. 2021 Oct 28;184(22):5653-5669.e25. (PMID: 34672952)
Science. 2008 Mar 28;319(5871):1793-4. (PMID: 18369139)
Comput Struct Biotechnol J. 2021 Mar 26;19:1684-1693. (PMID: 33897976)
Commun Biol. 2023 Apr 20;6(1):435. (PMID: 37081156)
Nat Cell Biol. 2006 Jan;8(1):91-9. (PMID: 16341205)
Nucleic Acids Res. 2017 Nov 2;45(19):e163. (PMID: 28977529)
Nat Methods. 2016 Oct;13(10):855-7. (PMID: 27525976)
Genome Biol. 2019 Dec 18;20(1):282. (PMID: 31847870)
Nat Commun. 2018 Apr 12;9(1):1418. (PMID: 29651020)
Comput Biol Chem. 2012 Dec;41:1-9. (PMID: 23142668)
Genome Biol. 2015 Dec 01;16:259. (PMID: 26619908)
Mol Cell. 2016 Jun 2;62(5):668-80. (PMID: 27259200)
Genome Biol. 2023 Apr 24;24(1):90. (PMID: 37095580)
Bioinformatics. 2021 Apr 20;37(3):422-423. (PMID: 32745185)
FEBS Lett. 2015 Oct 7;589(20 Pt A):2877-84. (PMID: 26348399)
Nat Methods. 2012 Oct;9(10):999-1003. (PMID: 22941365)
Nature. 2015 Feb 19;518(7539):331-6. (PMID: 25693564)
Cell. 2018 Feb 8;172(4):650-665. (PMID: 29425488)
Nucleic Acids Res. 2009 Jul;37(Web Server issue):W202-8. (PMID: 19458158)
Nature. 2019 Oct;574(7779):571-574. (PMID: 31645724)
Nat Commun. 2018 Aug 15;9(1):3265. (PMID: 30111883)

62173338 National Natural Science Foundation of China; 20220484198 Beijing Nova Program of Science and Technology

Keywords: 3D chromatin organization; DNA double-strand breaks (DSBs); TAD boundary; gene regulation; genomic stability; topologically associating domains (TADs)

0 (Chromatin)
0 (Transcription Factors)

Date Created: 20240627 Date Completed: 20240627 Latest Revision: 20240629

20240629

PMC11210073

10.1093/bib/bbae306

38935071