The Role of Spatial Organization of the Genome in the Regulation of Transcription
- Authors: Razin S.V.1,2
-
Affiliations:
- Institute of Gene Biology of the Russian Academy of Sciences
- Lomonosov Moscow State University
- Issue: Vol 61, No 11 (2025)
- Pages: 46–56
- Section: ОБЩИЕ ВОПРОСЫ И ТЕХНОЛОГИИ
- URL: https://journals.rcsi.science/0016-6758/article/view/361184
- DOI: https://doi.org/10.7868/S3034510325110065
- ID: 361184
Cite item
Abstract
The article considers the role of spatial organization of the genome in establishing communication between enhancers and promoters. Particular attention is paid to the genome-wide analysis of spatial contacts between enhancers and promoters and the identification of proteins involved in maintaining these contacts. The role of extrusion of chromatin loops by cohesin complexes in the movement of enhancers to target promoters is considered separately. The final part of the article analyzes problems that need to be solved. In particular, the question is considered of how close to the promoter in the physical space of the cell nucleus the enhancer should be to establish communication between these regulatory elements.
About the authors
S. V. Razin
Institute of Gene Biology of the Russian Academy of Sciences; Lomonosov Moscow State University
Email: sergey.v.razin@inbox.ru
Moscow, Russia
References
- Dekker J., Rippe K., Dekker M., Kleckner N. Capturing chromosome conformation // Science. 2002. V. 295. № 5558. P. 1306–1311.
- Cullen K.E., Kladde M.P., Seyfred M.A. Interaction between transcription regulatory regions of prolactin chromatin // Science. 1993. V. 261. № 5118. P. 203–206.
- Palstra R.J., Tolhuis B., Splinter E. et al. The beta-globin nuclear compartment in development and erythroid differentiation // Nat. Genet. 2003. V. 35. № 2. P. 190–194.
- Tolhuis B., Palstra R.J., Splinter E. et al. Looping and interaction between hypersensitive sites in the active beta-globin locus // Mol. Cell. 2002. V. 10. № 6. P. 1453–1465. https://doi.org/10.1016/S1097-2765(02)00781-5
- Vernimmen D., De Gobbi M., Sloane-Stanley J.A. et al. Long-range chromosomal interactions regulate the timing of the transition between poised and active gene expression // EMBO J. 2007. V. 26. № 8. P. 2041–2051. https://doi.org/10.1038/sj.emboj.7601654
- Vernimmen D., Marques-Kranc F., Sharpe J.A. et al. Chromosome looping at the human alpha-globin locus is mediated via the major upstream regulatory element (HS-40) // Blood. 2009. V. 114. № 19. P. 4253–4260. https://doi.org/10.1182/blood-2009-03-213439
- Philonenko E.S., Klochkov D.B., Borunova V.V. et al. TMEM8 – a non-globin gene entrapped in the globin web // Nucl. Acids Res. 2009. V. 37. № 22. P. 7394–7406. https://doi.org/10.1093/nar/gkp838
- Ulianov S.V., Gavrilov A.A., Razin S.V. Spatial organization of the chicken beta-globin gene domain in erythroid cells of embryonic and adult lineages // Epigenetics & Chromatin. 2012. V. 5. № 1. P. 16. https://doi.org/10.1186/1756-8935-5-16
- Williamson I., Berlivet S., Eskeland R. et al. Spatial genome organization: Contrasting views from chromosome conformation capture and fluorescence in situ hybridization // Genes Dev. 2014. V. 28. № 24. P. 2778–2791. https://doi.org/10.1101/gad.251694.114
- Williamson I., Lettice L.A., Hill R.E., Bickmore W.A. Shh and ZRS enhancer colocalisation is specific to the zone of polarising activity // Development. 2016. V. 143. № 16. P. 2994–3001. https://doi.org/10.1242/dev.139188
- Salem T., Gomard T., Court F. et al. Chromatin loop organization of the junb locus in mouse dendritic cells // Nucl. Acids Res. 2013. V. 41. № 19. P. 8908–8925. https://doi.org/10.1093/nar/gkt669
- Krivega I., Dean A. Chromatin looping as a target for altering erythroid gene expression // Ann. N.Y. Acad. Sci. 2016. V. 1368. № 1. P. 31–39. https://doi.org/10.1111/nyas.13012
- Breda L., Motta I., Lourenco S. et al. Forced chromatin looping raises fetal hemoglobin in adult sickle cells to higher levels than pharmacologic inducers // Blood. 2016. V. 128. № 8. P. 1139–1143. https://doi.org/10.1182/blood-2016-01-691089
- Deng W., Rupon J.W., Krivega I. et al. Reactivation of developmentally silenced globin genes by forced chromatin looping // Cell. 2014. V. 158. № 4. P. 849–860. https://doi.org/10.1016/j.cell.2014.05.050
- Razin S.V., Ulianov S.V., Iarovaia O.V. Enhancer function in the 3D genome // Genes (Basel). 2023. V. 14. № 6. https://doi.org/10.3390/genes14061277
- Yang J.H., Hansen A.S. Enhancer selectivity in space and time: From enhancer-promoter interactions to promoter activation // Nat. Rev. Mol. Cell. Biol. 2024. V. 25. № 7. P. 574–591. https://doi.org/10.1038/s41580-024-00710-6
- Hamamoto K., Fukaya T. Molecular architecture of enhancer-promoter interaction // Curr. Opin. Cell. Biol. 2022. V. 74. P. 62–70. https://doi.org/10.1016/j.ceb.2022.01.003
- Ulianov S.V., Zakharova V.V., Galitsyna A.A. et al. Order and stochasticity in the folding of individual Drosophila genomes // Nat. Commun. 2021. V. 12. № 1. P. 41. https://doi.org/10.1038/s41467-020-20292-z
- Dixon J.R., Gorkin D.U., Ren B. Chromatin domains: The unit of chromosome organization // Mol. Cell. 2016. V. 62. № 5. P. 668–680. https://doi.org/10.1016/j.molcel.2016.05.018
- Dixon J.R., Selvaraj S., Yue F. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions // Nature. 2012. V. 485. № 7398. С. 376–380. https://doi.org/10.1038/nature11082
- Sexton T., Yaffe E., Kenigsberg E. et al. Three-dimensional folding and functional organization principles of the Drosophila genome // Cell. 2012. V. 148. № 3. P. 458–472. https://doi.org/10.1016/j.cell.2012.01.010
- Nora E.P., Lajoie B.R., Schulz E.G. et al. Spatial partitioning of the regulatory landscape of the X-inactivation centre // Nature. 2012. V. 485. № 7398. P. 381–385. https://doi.org/10.1038/nature11049
- Valton A.L., Dekker J. TAD disruption as oncogenic driver // Curr. Opin. Genet. Dev. 2016. V. 36. P. 34–40. https://doi.org/10.1016/j.gde.2016.03.008
- Tiukacheva E.A., Ulianov S.V., Karpukhina A. et al. 3D genome alterations and editing in pathology // Mol. Ther. 2023. V. 31. № 4. P. 924–933. https://doi.org/10.1016/j.ymthe.2023.02.005
- Franke M., Ibrahim D.M., Andrey G. et al. Formation of new chromatin domains determines pathogenicity of genomic duplications // Nature. 2016. V. 538. № 7624. P. 265–269. https://doi.org/10.1038/nature19800
- Lupianez D.G., Kraft K., Heinrich V. et al. Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions // Cell. 2015. V. 161. № 5. P. 1012–1025. https://doi.org/10.1016/j.cell.2015.04.004
- Lupianez D.G., Spielmann M., Mundlos S. Breaking TADs: How alterations of chromatin domains result in disease // Trends Genet. 2016. V. 32. № 4. P. 225–237. https://doi.org/10.1016/j.tig.2016.01.003
- Sanborn A.L., Rao S.S., Huang S.C. et al. Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes // Proc. Natl Acad. Sci. USA. 2015. V. 112. № 47. P. E6456–E6465. https://doi.org/10.1073/pnas.1518552112
- Fudenberg G., Imakaev M., Lu C. et al. Formation of chromosomal domains by loop extrusion // Cell Rep. 2016. V. 15. № 9. P. 2038–2049. https://doi.org/10.1016/j.celrep.2016.04.085
- Wutz G., Varnai C., Nagasaka K. et al. Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins // EMBO J. 2017. V. 36. № 24. P. 3573–3599. https://doi.org/10.15252/embj.201798004
- Bintu B., Mateo L.J., Su J.H. et al. Super-resolution chromatin tracing reveals domains and cooperative interactions in single cells // Science. 2018. T. 362. № 6413. https://doi.org/10.1126/science.aau1783
- Palstra R.J. Close encounters of the 3C kind: Longrange chromatin interactions and transcriptional regulation // Brief. Funct. Genomic Proteomic. 2009. V. 8. № 4. P. 297–309. 33. Holwerda S., de Laat W. Chromatin loops, gene positioning, and gene expression // Front. Genet. 2012. V. 3. https://doi.org/10.3389/fgene.2012.00217
- Li X., Levine M. What are tethering elements? // Curr. Opin. Genet. Dev. 2024. V. 84. https://doi.org/10.1016/j.gde.2023.102151
- Calhoun V.C., Levine M. Long-range enhancer-promoter interactions in the Scr-Antp interval of the Drosophila antennapedia complex // Proc. Natl Acad. Sci. USA. 2003. V. 100. № 17. P. 9878–9883. https://doi.org/10.1073/pnas.1233791100
- Harke J., Lee J.R., Nguyen S.C. et al. Multiple allelic configurations govern long-range Shh enhancer-promoter communication in the embryonic forebrain // Mol. Cell. 2024. V. 84. № 24. P. 4698–4710. https://doi.org/10.1016/j.molcel.2024.10.042
- Golov A.K., Gavrilov A.A., Kaplan N., Razin S.V. A genome-wide nucleosome-resolution map of promoter-centered interactions in human cells corroborates the enhancer-promoter looping model // Elife. 2024. V. 12. https://doi.org/10.7554/eLife.91596
- Hsieh T.H., Weiner A., Lajoie B. et al. Mapping nucleosome resolution chromosome folding in yeast by Micro-C // Cell. 2015. V. 162. № 1. P. 108–119. https://doi.org/10.1016/j.cell.2015.05.048
- Fulco C.P., Munschauer M., Anyoha R. et al. Systematic mapping of functional enhancer-promoter connections with CRISPR interference // Science. 2016. V. 354. № 6313. P. 769–773. https://doi.org/10.1126/science.aag2445
- Shukla A., Huangfu D. Decoding the noncoding genome via large-scale CRISPR screens // Curr. Opin. Genet. Dev. 2018. V. 52. P. 70–76. https://doi.org/10.1016/j.gde.2018.06.001
- Gasperini M., Hill A.J., McFaline-Figueroa J.L. et al. A genome-wide framework for mapping gene regulation via cellular genetic screens // Cell. 2019. V. 176. № 1–2. P. 377–390. https://doi.org/10.1016/j.cell.2018.11.029
- Fulco C.P., Nasser J., Jones T.R. et al. Activity-by-contact model of enhancer-promoter regulation from thousands of CRISPR perturbations // Nat. Genet. 2019. V. 51. № 12. P. 1664–1669. https://doi.org/10.1038/s41588-019-0538-0
- Murphy D., Salataj E., Di Giammartino D.C. et al. 3D enhancer-promoter networks provide predictive features for gene expression and coregulation in early embryonic lineages // Nat. Struct. Mol. Biol. 2024. V. 31. № 1. P. 125–140. https://doi.org/10.1038/s41594-023-01130-4
- Zhu Y., Rosenfeld M.G., Suh Y. Ultrafine mapping of chromosome conformation at hundred basepair resolution reveals regulatory genome architecture // Proc. Natl Acad. Sci. USA. 2023. V. 120. № 45. https://doi.org/10.1073/pnas.2313285120
- Dekker J., Mirny L. The 3D Genome as moderator of chromosomal communication // Cell. 2016. V. 164. № 6. P. 1110–1121. https://doi.org/10.1016/j.cell.2016.02.007
- Lucas J.S., Zhang Y., Dudko O.K., Murre C. 3D trajectories adopted by coding and regulatory DNA elements: First-passage times for genomic interactions // Cell. 2014. V. 158. № 2. P. 339–352. https://doi.org/10.1016/j.cell.2014.05.036
- Valton A.L., Venev S.V., Mair B. et al. A cohesin traffic pattern genetically linked to gene regulation // Nat. Struct. Mol. Biol. 2022. V. 29. № 12. P. 1239–1251. https://doi.org/10.1038/s41594-022-00890-9
- Rinzema N.J., Sofiadis K., Tjalsma S.J.D. et al. Building regulatory landscapes reveals that an enhancer can recruit cohesin to create contact domains, engage CTCF sites and activate distant genes // Nat. Struct. Mol. Biol. 2022. V. 29. № 6. P. 563–574. https://doi.org/10.1038/s41594-022-00787-7
- Vos E.S.M., Valdes-Quezada C., Huang Y. et al. Interplay between CTCF boundaries and a super enhancer controls cohesin extrusion trajectories and gene expression // Mol. Cell. 2021. V. 81. № 15. P. 3082–3095. https://doi.org/10.1016/j.molcel.2021.06.008
- Kane L., Williamson I., Flyamer I.M. et al. Cohesin is required for long-range enhancer action at the Shh locus // Nat. Struct. Mol. Biol. 2022. V. 29. № 9. P. 891–897. https://doi.org/10.1038/s41594-022-00821-8
- Guckelberger P., Doughty B.R., Munson G. et al. Cohesin-mediated 3D contacts tune enhancer-promoter regulation // bioRxiv. 2024. https://doi.org/10.1101/2024.07.12.603288
- Golov A.K., Gavrilov A.A. Cohesin-dependent loop extrusion: Molecular mechanics and role in cell physiology // Biochemistry (Mosc.). 2024. V. 89. № 4. P. 601–625. https://doi.org/10.1134/S0006297924040023
- Golov A.K., Gavrilov A.A. Cohesin complex: Structure
- and principles of interaction with DNA // Biochemistry (Mosc). 2024. V. 89. № 4. P. 585–600. https://doi.org/10.1134/S0006297924040011
- Kim Y., Shi Z., Zhang H. et al. Human cohesin compacts DNA by loop extrusion // Science. 2019. V. 366. № 6471. P. 1345–1349. https://doi.org/10.1126/science.aaz4475
- Galitsyna A., Ulianov S.V., Bykov N.S. et al. Extrusion fountains are hallmarks of chromosome organization emerging upon zygotic genome activation // bioRxiv. 2023. https://doi.org/10.1101/2023.07.15.549120
- Ing-Simmons E., Seitan V.C., Faure A.J. et al. Spatial enhancer clustering and regulation of enhancer-proximal genes by cohesin // Genome Res. 2015. V. 25. № 4. P. 504–513. https://doi.org/10.1101/gr.184986.114
- Fursova N.A., Larson D.R. Transcriptional machinery as an architect of genome structure // Curr. Opin. Struct. Biol. 2024. V. 89. https://doi.org/10.1016/j.sbi.2024.102920
- Kubo N., Ishii H., Xiong X. et al. Promoter-proximal CTCF binding promotes distal enhancer-dependent gene activation // Nat. Struct. Mol. Biol. 2021. V. 28. № 2. P. 152–161. https://doi.org/10.1038/s41594-020-00539-5
- Ren G., Jin W., Cui K. et al. CTCF-mediated enhancer-promoter interaction is a critical regulator of cell-to-cell variation of gene expression // Mol. Cell. 2017. V. 67. № 6. P. 1049–1058 e1046. https://doi.org/10.1016/j.molcel.2017.08.026
- Banigan E.J., Tang W., van den Berg A.A. et al. Transcription shapes 3D chromatin organization by interacting with loop extrusion // Proc. Natl Acad. Sci. USA. 2023. V. 120. № 11. https://doi.org/10.1073/pnas.2210480120
- Zhang S., Ubelmesser N., Barbieri M., Papantonis A. Enhancer-promoter contact formation requires RNAPII and antagonizes loop extrusion // Nat. Genet. 2023. V. 55. № 5. P. 832–840. https://doi.org/10.1038/s41588-023-01364-4
- Brandao H.B., Paul P., van den Berg A.A. et al. RNA polymerases as moving barriers to condensin loop extrusion // Proc. Natl Acad. Sci. USA. 2019. V. 116. № 41. P. 20489–20499. https://doi.org/10.1073/pnas.1907009116
- Hsieh T.S., Cattoglio C., Slobodyanyuk E. et al. Enhancer-promoter interactions and transcription are largely maintained upon acute loss of CTCF, cohesin, WAPL or YY1 // Nat. Genet. 2022. V. 54. № 12. P. 1919–1932. https://doi.org/10.1038/s41588-022-01223-8
- Rao S.S.P., Huang S.C., Glenn St Hilaire B. et al. Cohesin loss eliminates all loop domains // Cell. 2017. V. 171. № 2. P. 305–320. https://doi.org/10.1016/j.cell.2017.09.026
- Schwarzer W., Abdennur N., Goloborodko A. et al. Two independent modes of chromatin organization revealed by cohesin removal // Nature. 2017. V. 551. № 7678. P. 51–56. https://doi.org/10.1038/nature24281
- Ulianov S.V., Velichko A.K., Magnitov M.D. et al. Suppression of liquid-liquid phase separation by 1,6-hexanediol partially compromises the 3D genome organization in living cells // Nucl. Acids Res. 2021. V. 49. № 18. P. 10524–10541. https://doi.org/10.1093/nar/gkab249
- Oo J.A., Warwick T., Palfi K. et al. Long non-coding RNAs direct the SWI/SNF complex to cell type-specific enhancers // Nat. Commun. 2025. V. 16. № 1. P. 131. https://doi.org/10.1038/s41467-024-55539-6
- Serra F., Nieto-Aliseda A., Fanlo-Escudero L. et al. p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response // Nat. Commun. 2024. V. 15. № 1. P. 2821. https://doi.org/10.1038/s41467-024-46666-1
- Rubio L.S., Mohajan S., Gross D.S. Heat shock factor 1 forms nuclear condensates and restructures the yeast genome before activating target genes // Elife. 2024. V. 12. https://doi.org/10.7554/eLife.92464
- Chowdhary S., Kainth A.S., Paracha S. et al. Inducible transcriptional condensates drive 3D genome reorganization in the heat shock response // Mol. Cell. 2022. V. 82. № 22. P. 4386–4399 e4387. https://doi.org/10.1016/j.molcel.2022.10.013
- De Laat W., Grosveld F. Spatial organization of gene expression: The active chromatin hub // Chromosome Res. 2003. V. 11. P. 447–459.
- Gavrilov A.A., Gushchanskaya E.S., Strelkova O. et al. Disclosure of a structural milieu for the proximity ligation reveals the elusive nature of an active chromatin hub // Nucl. Acids Res. 2013. V. 41. № 6. P. 3563–3575. https://doi.org/10.1093/nar/gkt067
- Gavrilov A., Eivazova E., Priozhkova I. et al. Chromosome conformation capture (from 3C to 5C) and its ChIP-based modification // Methods Mol. Biol. 2009. V. 567. P. 171–188.
- De Wit E., de Laat W. A decade of 3C technologies: Insights into nuclear organization // Genes Dev. 2012. V. 26. № 1. P. 11–24.
- Denker A., de Laat W. The second decade of 3C technologies: Detailed insights into nuclear organization // Genes Dev. 2016. V. 30. № 12. P. 1357–1382. https://doi.org/10.1101/gad.281964.116
- Gavrilov A.A., Chetverina H.V., Chermnykh E.S. et al. Quantitative analysis of genomic element interactions by molecular colony technique // Nucl. Acids Res. 2014. V. 42. № 5. P. e36. https://doi.org/10.1093/nar/gkt1322
- Gavrilov A.A., Golov A.K., Razin S.V. Actual ligation frequencies in the chromosome conformation capture procedure // PLoS One. 2013. V. 8. № 3. https://doi.org/10.1371/journal.pone.0060403
- Heist T., Fukaya T., Levine M. Large distances separate coregulated genes in living Drosophila embryos // Proc. Natl Acad. Sci. USA. 2019. V. 116. № 30. P. 15062–15067. https://doi.org/10.1073/pnas.1908962116
- Chen H., Levo M., Barinov L. et al. Dynamic interplay between enhancer-promoter topology and gene activity // Nat. Genet. 2018. V. 50. № 9. P. 1296–1303. https://doi.org/10.1038/s41588-018-0175-z
- Li J., Hsu A., Hua Y. et al. Single-gene imaging links genome topology, promoter-enhancer communication and transcription control // Nat. Struct. Mol. Biol. 2020. V. 27. № 11. P. 1032–1040. https://doi.org/10.1038/s41594-020-0493-6
- Thiecke M.J., Wutz G., Muhar M. et al. Cohesin-dependent and -independent mechanisms mediate chromosomal contacts between promoters and enhancers // Cell Rep. 2020. V. 32. № 3. https://doi.org/10.1016/j.celrep.2020.107929
- Karr J.P., Ferrie J.J., Tjian R., Darzacq X. The transcription factor activity gradient (TAG) model: Contemplating a contact-independent mechanism for enhancer-promoter communication // Genes Dev. 2022. V. 36. № 1–2. P. 7–16. https://doi.org/10.1101/gad.349160.121
- Wurmser A., Basu S. Enhancer-promoter communication: It's not just about contact // Front. Mol. Biosci. 2022. V. 9. https://doi.org/10.3389/fmolb.2022.867303
Supplementary files


