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Three-dimensional genome organization in immune cell fate and function

Abstract

Immune cell development and activation demand the precise and coordinated control of transcriptional programmes. Three-dimensional (3D) organization of the genome has emerged as an important regulator of chromatin state, transcriptional activity and cell identity by facilitating or impeding long-range genomic interactions among regulatory elements and genes. Chromatin folding thus enables cell type-specific and stimulus-specific transcriptional responses to extracellular signals, which are essential for the control of immune cell fate, for inflammatory responses and for generating a diverse repertoire of antigen receptor specificities. Here, we review recent findings connecting 3D genome organization to the control of immune cell differentiation and function, and discuss how alterations in genome folding may lead to immune dysfunction and malignancy.

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Fig. 1: Hierarchical 3D chromatin organization.
Fig. 2: Immune cell differentiation and specification.
Fig. 3: Changes in genome topology during immune cell differentiation.
Fig. 4: Different genome folding dynamics underlie innate and adaptive immune responses.
Fig. 5: Aberrant genome folding in immune disorders and leukaemia.

References

  1. Nicholson, L. B. The immune system. Essays Biochem. 60, 275 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Hosokawa, H. & Rothenberg, E. V. How transcription factors drive choice of the T cell fate. Nat. Rev. Immunol. 21, 162–176 (2021).

    Article  CAS  PubMed  Google Scholar 

  3. Smale, S. T. & Natoli, G. Transcriptional control of inflammatory responses. Cold Spring Harb. Perspect. Biol. 6, a016261 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Pulendran, B. & Davis, M. M. The science and medicine of human immunology. Science 369, eaay4014 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Stadhouders, R., Filion, G. J. & Graf, T. Transcription factors and 3D genome conformation in cell-fate decisions. Nature 569, 345–354 (2019).

    Article  CAS  PubMed  Google Scholar 

  6. Grosveld, F., Van Staalduinen, J. & Stadhouders, R. Transcriptional regulation by (super)enhancers: from discovery to mechanisms. Annu. Rev. Genomics Hum. Genet. 22, 127–146 (2021).

    Article  PubMed  CAS  Google Scholar 

  7. Oudelaar, A. M. & Higgs, D. R. The relationship between genome structure and function. Nat. Rev. Genet. 22, 154–168 (2021).

    Article  CAS  PubMed  Google Scholar 

  8. Furlong, E. E. M. M. & Levine, M. Developmental enhancers and chromosome topology. Science 361, 1341–1345 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhu, H., Wang, G. & Qian, J. Transcription factors as readers and effectors of DNA methylation. Nat. Rev. Genet. 17, 551–565 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Voss, T. C. & Hager, G. L. Dynamic regulation of transcriptional states by chromatin and transcription factors. Nat. Rev. Genet. 15, 69–81 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. de Laat, W. & Dekker, J. 3C-based technologies to study the shape of the genome. Methods 58, 189–191 (2012).

    Article  PubMed  CAS  Google Scholar 

  12. Jerković, I. & Cavalli, G. Understanding 3D genome organization by multidisciplinary methods. Nat. Rev. Mol. Cell Biol. 22, 511–528 (2021).

    Article  PubMed  CAS  Google Scholar 

  13. Rowley, M. J. & Corces, V. G. Organizational principles of 3D genome architecture. Nat. Rev. Genet. 19, 789–800 (2018).

    Article  CAS  PubMed  Google Scholar 

  14. Bonev, B. & Cavalli, G. Organization and function of the 3D genome. Nat. Rev. Genet. 17, 661–678 (2016).

    Article  CAS  PubMed  Google Scholar 

  15. Rao, S. S. et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159, 1665–1680 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Vilarrasa-Blasi, R. et al. Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation. Nat. Commun. 12, 651 (2021). This report characterizes 3D genome dynamics during human B cell differentiation and transformation, uncovering a plastic intermediate ‘I’ chromatin compartment type enriched in poised and Polycomb-repressed chromatin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Vian, L. et al. The energetics and physiological impact of cohesin extrusion. Cell 173, 1165–1178.e20 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Barrington, C. et al. Enhancer accessibility and CTCF occupancy underlie asymmetric TAD architecture and cell type specific genome topology. Nat. Commun. 10, 1–14 (2019).

    Article  CAS  Google Scholar 

  19. Kraft, K. et al. Serial genomic inversions induce tissue-specific architectural stripes, gene misexpression and congenital malformations. Nat. Cell Biol. 21, 305–310 (2019).

    Article  CAS  PubMed  Google Scholar 

  20. Hsieh, T. H. S. et al. Resolving the 3D landscape of transcription-linked mammalian chromatin folding. Mol. Cell 78, 539–553.e8 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Davidson, I. F. & Peters, J. M. Genome folding through loop extrusion by SMC complexes. Nat. Rev. Mol. Cell Biol. 22, 445–464 (2021).

    Article  CAS  PubMed  Google Scholar 

  22. Andrey, G. & Mundlos, S. The three-dimensional genome: regulating gene expression during pluripotency and development. Development 144, 3646–3658 (2017).

    Article  CAS  PubMed  Google Scholar 

  23. Schoenfelder, S. & Fraser, P. Long-range enhancer–promoter contacts in gene expression control. Nat. Rev. Genet. 20, 437–455 (2019).

    Article  CAS  PubMed  Google Scholar 

  24. Hyman, A. A., Weber, C. A. & Jülicher, F. Liquid-liquid phase separation in biology. Annu. Rev. Cell Dev. Biol. 30, 39–58 (2014).

    Article  CAS  PubMed  Google Scholar 

  25. Hnisz, D., Shrinivas, K., Young, R. A., Chakraborty, A. K. & Sharp, P. A. A phase separation model for transcriptional control. Cell 169, 13–23 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Maeshima, K., Ide, S., Hibino, K. & Sasai, M. Liquid-like behavior of chromatin. Curr. Opin. Genet. Dev. 37, 36–45 (2016).

    Article  CAS  PubMed  Google Scholar 

  27. Zenk, F. et al. HP1 drives de novo 3D genome reorganization in early Drosophila embryos. Nature 593, 289 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Strom, A. R. et al. Phase separation drives heterochromatin domain formation. Nature 547, 241–245 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Larson, A. G. et al. Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin. Nature 547, 236–240 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sabari, B. R., Dall’Agnese, A. & Young, R. A. Biomolecular condensates in the nucleus. Trends Biochem. Sci. 45, 961–977 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hildebrand, E. M. & Dekker, J. Mechanisms and functions of chromosome compartmentalization. Trends Biochem. Sci. 45, 385–396 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Huang, Y., Neijts, R. & de Laat, W. How chromosome topologies get their shape: views from proximity ligation and microscopy methods. FEBS Lett. 594, 3439–3449 (2020).

    Article  CAS  PubMed  Google Scholar 

  33. McCord, R. P., Kaplan, N. & Giorgetti, L. Chromosome conformation capture and beyond: toward an integrative view of chromosome structure and function. Mol. Cell 77, 688–708 (2020).

    Article  CAS  PubMed  Google Scholar 

  34. Ibrahim, D. M. & Mundlos, S. The role of 3D chromatin domains in gene regulation: a multi-facetted view on genome organization. Curr. Opin. Genet. Dev. 61, 1–8 (2020).

    Article  CAS  PubMed  Google Scholar 

  35. Robson, M. I., Ringel, A. R. & Mundlos, S. Regulatory landscaping: how enhancer–promoter communication is sculpted in 3D. Mol. Cell 74, 1110–1122 (2019).

    Article  CAS  PubMed  Google Scholar 

  36. Morgan, S. L. et al. Manipulation of nuclear architecture through CRISPR-mediated chromosomal looping. Nat. Commun. 8, 1–9 (2017).

    Article  CAS  Google Scholar 

  37. Wang, H. et al. CRISPR-mediated programmable 3D genome positioning and nuclear organization. Cell 175, 1405–1417.e14 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kim, J. H. et al. LADL: light-activated dynamic looping for endogenous gene expression control. Nat. Methods 16, 633–639 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Wang, J. et al. Phase separation of OCT4 controls TAD reorganization to promote cell fate transitions. Cell Stem Cell 28, 1868–1883.e11 (2021).

    Article  CAS  PubMed  Google Scholar 

  40. Rada‐Iglesias, A., Grosveld, F. G. & Papantonis, A. Forces driving the three-dimensional folding of eukaryotic genomes. Mol. Syst. Biol. 14, 8214 (2018).

    Article  CAS  Google Scholar 

  41. Zhang, S., Übelmesser, N., Barbieri, M. & Papantonis, A. Enhancer–promoter contact formation requires RNAPII and antagonizes loop extrusion. Preprint at bioRxiv https://doi.org/10.1101/2022.07.04.498738 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Barshad, G. et al. RNA polymerase II and PARP1 shape enhancer–promoter contacts. Preprint at bioRxiv https://doi.org/10.1101/2022.07.07.499190 (2022).

    Article  Google Scholar 

  43. Yoshida, H. et al. The cis-regulatory atlas of the mouse immune system. Cell 176, 897–912.e20 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chen, C. et al. Spatial genome re-organization between fetal and adult hematopoietic stem cells. Cell Rep. 29, 4200–4211.e7 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhang, X. et al. Large DNA methylation nadirs anchor chromatin loops maintaining hematopoietic stem cell identity. Mol. Cell 78, 506–521.e6 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang, C. et al. tagHi-C reveals 3D chromatin architecture dynamics during mouse hematopoiesis. Cell Rep. 32, 108206 (2020).

    Article  CAS  PubMed  Google Scholar 

  47. Willcockson, M. A. et al. H1 histones control the epigenetic landscape by local chromatin compaction. Nature 589, 293–298 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Zhu, Y. et al. Comprehensive characterization of neutrophil genome topology. Genes Dev. 31, 141–153 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhou, Q. et al. ZNF143 mediates CTCF-bound promoter–enhancer loops required for murine hematopoietic stem and progenitor cell function. Nat. Commun. 12, 43 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Boya, R. et al. Developmentally regulated higher-order chromatin interactions orchestrate B cell fate commitment. Nucleic Acids Res. 45, 11070–11087 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Johanson, T. M. et al. Transcription-factor-mediated supervision of global genome architecture maintains B cell identity. Nat. Immunol. 19, 1257–1264 (2018). This comprehensive study of genome topology during mouse B cell differentiation and specification shows a critical role for a lineage-determining transcription factor in shaping 3D genome folding in primary immune cells.

    Article  CAS  PubMed  Google Scholar 

  52. Lin, Y. C. et al. Global changes in the nuclear positioning of genes and intra- and interdomain genomic interactions that orchestrate B cell fate. Nat. Immunol. 13, 1196–1204 (2012). This classic Hi-C study describes A/B compartment characteristics and dynamics in differentiating mouse B cells, revealing different types of DNA-binding proteins associated with chromatin interactions at different length scales.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hill, L. et al. Wapl repression by Pax5 promotes V gene recombination by Igh loop extrusion. Nature 584, 142–147 (2020). This elegant study shows that Pax5 promotes immunoglobulin heavy chain (IgH) locus contraction by directly controlling the levels of cohesin-release factor Wapl, demonstrating that dynamic control of 3D genome folding is critical for generating a diverse antibody repertoire in mouse B cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Medvedovic, J. et al. Flexible long-range loops in the VH gene region of the igh locus facilitate the generation of a diverse antibody repertoire. Immunity 39, 229 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Stadhouders, R. et al. Pre-B cell receptor signaling induces immunoglobulin κ locus accessibility by functional redistribution of enhancer-mediated chromatin interactions. PLoS Biol. 12, e1001791 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Ribeiro de Almeida, C. et al. The DNA-binding protein CTCF limits proximal Vκ recombination and restricts κ enhancer interactions to the immunoglobulin κ light chain locus. Immunity 35, 501–513 (2011).

    Article  CAS  PubMed  Google Scholar 

  57. Guo, C. et al. CTCF-binding elements mediate control of V(D)J recombination. Nature 477, 424–430 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Isoda, T. et al. Non-coding transcription instructs chromatin folding and compartmentalization to dictate enhancer–promoter communication and T cell fate. Cell 171, 103–119.e18 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Collins, A. et al. RUNX transcription factor-mediated association of Cd4 and Cd8 enables coordinate gene regulation. Immunity 34, 303–314 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hu, G. et al. Transformation of accessible chromatin and 3D nucleome underlies lineage commitment of early T cells. Immunity 48, 227–242.e8 (2018). This work is the first comprehensive analysis of 3D genome architecture in developing T cells from the murine thymus, implicating the Bcl11b transcription factor in shaping topological genome dynamics.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Miyazaki, K. et al. The transcription factor E2A activates multiple enhancers that drive Rag expression in developing T and B cells. Sci. Immunol. 5, eabb1455 (2020).

    Article  CAS  PubMed  Google Scholar 

  62. Ing-Simmons, E. et al. Spatial enhancer clustering and regulation of enhancer-proximal genes by cohesin. Genome Res. 25, 504 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Seitan, V. C. et al. A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation. Nature 476, 467–473 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Shih, H. Y. et al. Tcra gene recombination is supported by a Tcra enhancer- and CTCF-dependent chromatin hub. Proc. Natl Acad. Sci. USA 109, E3493–E3502 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wang, W. et al. TCF-1 promotes chromatin interactions across topologically associating domains in T cell progenitors. Nat. Immunol. 23, 1052–1062 (2022).

    Article  CAS  PubMed  Google Scholar 

  66. Cai, S., Han, H. J. & Kohwi-Shigematsu, T. Tissue-specific nuclear architecture and gene expession regulated by SATB1. Nat. Genet. 34, 42–51 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Placek, K. et al. MLL4 prepares the enhancer landscape for Foxp3 induction via chromatin looping. Nat. Immunol. 18, 1035–1045 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Stadhouders, R. et al. Transcription factors orchestrate dynamic interplay between genome topology and gene regulation during cell reprogramming. Nat. Genet. 50, 238–249 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Minderjahn, J. et al. Postmitotic differentiation of human monocytes requires cohesin-structured chromatin. Nat. Commun. 13, 1–19 (2022).

    Article  CAS  Google Scholar 

  70. Stik, G. et al. CTCF is dispensable for immune cell transdifferentiation but facilitates an acute inflammatory response. Nat. Genet. 52, 655–661 (2020). This work is the first study showing that lineage conversion of human immune cells does not critically depend on CTCF and TAD architecture, which do play an important context-specific role in optimizing acute transcriptional responses to inflammatory cues.

    Article  CAS  PubMed  Google Scholar 

  71. Medzhitov, R. Origin and physiological roles of inflammation. Nature 454, 428–435 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Bhatt, D. M. et al. Transcript dynamics of proinflammatory genes revealed by sequence analysis of subcellular RNA fractions. Cell 150, 279–290 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Escoubet-Lozach, L. et al. Mechanisms establishing TLR4-responsive activation states of inflammatory response genes. PLoS Genet. 7, e1002401 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ostuni, R. et al. Latent enhancers activated by stimulation in differentiated cells. Cell 152, 157–171 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Kaikkonen, M. U. et al. Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. Mol. Cell 51, 310–325 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Glass, C. K. & Natoli, G. Molecular control of activation and priming in macrophages. Nat. Immunol. 17, 26–33 (2015).

    Article  PubMed Central  CAS  Google Scholar 

  78. Santiago-Algarra, D. et al. Epromoters function as a hub to recruit key transcription factors required for the inflammatory response. Nat. Commun. 12, 1–18 (2021).

    Article  CAS  Google Scholar 

  79. Jin, F. et al. A high-resolution map of the three-dimensional chromatin interactome in human cells. Nature 503, 290–294 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Denholtz, M. et al. Upon microbial challenge, human neutrophils undergo rapid changes in nuclear architecture and chromatin folding to orchestrate an immediate inflammatory gene program. Genes Dev. 34, 149–165 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Vangala, P. et al. High-resolution mapping of multiway enhancer–promoter interactions regulating pathogen detection. Mol. Cell 80, 359–373.e8 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kolovos, P. et al. Binding of nuclear factor κB to noncanonical consensus sites reveals its multimodal role during the early inflammatory response. Genome Res. 26, 1478–1489 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Platanitis, E. et al. Interferons reshape the 3D conformation and accessibility of macrophage chromatin. iScience 25, 103840 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Zhu, Y., Denholtz, M., Lu, H. & Murre, C. Calcium signaling instructs NIPBL recruitment at active enhancers and promoters via distinct mechanisms to reconstruct genome compartmentalization. Genes Dev. 35, 65–81 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Phanstiel, D. H. et al. Static and dynamic DNA loops form AP-1-bound activation hubs during macrophage development. Mol. Cell 67, 1037–1048.e6 (2017). This study characterizes 3D genome changes during human macrophage activation, identifying AP1 transcription factors as putative drivers of dynamic chromatin loop formation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Reed, K. S. M. et al. Temporal analysis suggests a reciprocal relationship between 3D chromatin structure and transcription. Preprint at bioRxiv https://doi.org/10.1101/2022.05.05.490836 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Fanucchi, S. et al. Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments. Nat. Genet. 51, 138–150 (2019). This paper identifies a new mechanism underlying trained immunity involving a specialized class of long ncRNAs that prime inflammatory genes through 3D chromatin interactions, which is facilitated by TAD structure.

    Article  CAS  PubMed  Google Scholar 

  88. Weiterer, S. et al. Distinct IL-1α-responsive enhancers promote acute and coordinated changes in chromatin topology in a hierarchical manner. EMBO J. 39, e101533 (2020).

    Article  CAS  PubMed  Google Scholar 

  89. Papantonis, A. et al. TNFα signals through specialized factories where responsive coding and miRNA genes are transcribed. EMBO J. 31, 4404–4414 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Cuartero, S. et al. Control of inducible gene expression links cohesin to hematopoietic progenitor self-renewal and differentiation. Nat. Immunol. 19, 932–941 (2018). This study shows that cohesin is preferentially required for inducible gene transcription, resulting in a blunted inflammatory response of cohesin-deficient haematopoietic stem and progenitor cells and macrophages.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Chen, Z. et al. Cohesin-mediated NF-κB signaling limits hematopoietic stem cell self-renewal in aging and inflammation. J. Exp. Med. 216, 152–175 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Robles-Rebollo, I. et al. Cohesin couples transcriptional bursting probabilities of inducible enhancers and promoters. Nat. Commun. 13, 1–16 (2022).

    Article  CAS  Google Scholar 

  93. Siwek, W., Tehrani, S. S. H., Mata, J. F. & Jansen, L. E. T. Activation of clustered IFNγ target genes drives cohesin-controlled transcriptional memory. Mol. Cell 80, 396–409.e6 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Rawlings, J. S., Gatzka, M., Thomas, P. G. & Ihle, J. N. Chromatin condensation via the condensin II complex is required for peripheral T-cell quiescence. EMBO J. 30, 263–276 (2011).

    Article  CAS  PubMed  Google Scholar 

  95. Yusufova, N. et al. Histone H1 loss drives lymphoma by disrupting 3D chromatin architecture. Nature 589, 299–305 (2020). This paper demonstrates that H1 mutations can drive lymphoma formation by promoting 3D chromatin decompaction and derepression of stem cell genes that are normally silenced during differentiation.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Buck, M. D., O’Sullivan, D. & Pearce, E. L. T cell metabolism drives immunity. J. Exp. Med. 212, 1345–1360 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Naito, T., Tanaka, H., Naoe, Y. & Taniuchi, I. Transcriptional control of T-cell development. Int. Immunol. 23, 661–668 (2011).

    Article  CAS  PubMed  Google Scholar 

  98. De Silva, N. S. & Klein, U. Dynamics of B cells in germinal centres. Nat. Rev. Immunol. 15, 137–148 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Shan, Q. et al. Tcf1–CTCF cooperativity shapes genomic architecture to promote CD8+ T cell homeostasis. Nat. Immunol. https://doi.org/10.1038/s41590-022-01263-6 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Javierre, B. M. et al. Lineage-specific genome architecture links enhancers and non-coding disease variants to target gene promoters. Cell 167, 1369–1384.e19 (2016). This landmark paper describes the genome-wide promoter interactome in several primary human haematopoietic cell types, allowing for disease-associated genetic variants to be linked to their putative target genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Mumbach, M. R. et al. Enhancer connectome in primary human cells identifies target genes of disease-associated DNA elements. Nat. Genet. 49, 1602–1612 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Burren, O. S. et al. Chromosome contacts in activated T cells identify autoimmune disease candidate genes. Genome Biol. 18, 1–19 (2017).

    Article  CAS  Google Scholar 

  103. Yang, J. et al. Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis. Nat. Commun. 11, 1–13 (2020).

    CAS  Google Scholar 

  104. Bediaga, N. G. et al. Multi-level remodelling of chromatin underlying activation of human T cells. Sci. Rep. 11, 1–16 (2021).

    Article  CAS  Google Scholar 

  105. He, B. et al. CD8+ T cells utilize highly dynamic enhancer repertoires and regulatory circuitry in response to infections. Immunity 45, 1341–1354 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lai, B. et al. Trac-looping measures genome structure and chromatin accessibility. Nat. Methods 15, 741–747 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kieffer-Kwon, K. R. et al. Myc regulates chromatin decompaction and nuclear architecture during B cell activation. Mol. Cell 67, 566–578.e10 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Robson, M. I. et al. Constrained release of lamina-associated enhancers and genes from the nuclear envelope during T-cell activation facilitates their association in chromosome compartments. Genome Res. 27, gr.212308.116 (2017).

    Article  CAS  Google Scholar 

  109. Schoonhoven, A., van, Huylebroeck, D., Hendriks, R. W. & Stadhouders, R. 3D genome organization during lymphocyte development and activation. Brief. Funct. Genomics 19, 71–82 (2020).

    Article  PubMed  CAS  Google Scholar 

  110. Stadhouders, R., Lubberts, E. & Hendriks, R. W. A cellular and molecular view of T helper 17 cell plasticity in autoimmunity. J. Autoimmun. 87, 1–15 (2018).

    Article  CAS  PubMed  Google Scholar 

  111. Zhu, J., Yamane, H. & Paul, W. E. Differentiation of effector CD4 T cell populations. Annu. Rev. Immunol. 28, 445 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Scourzic, L., Salataj, E. & Apostolou, E. Deciphering the complexity of 3D chromatin organization driving lymphopoiesis and lymphoid malignancies. Front. Immunol. 12, 669881 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Liu, S. & Zhao, K. The toolbox for untangling chromosome architecture in immune cells. Front. Immunol. 12, 1389 (2021).

    Google Scholar 

  114. Grogan, J. L. et al. Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets. Immunity 14, 205–215 (2001).

    Article  CAS  PubMed  Google Scholar 

  115. Hewitt, S. L., High, F. A., Reiner, S. L., Fisher, A. G. & Merkenschlager, M. Nuclear repositioning marks the selective exclusion of lineage-inappropriate transcription factor loci during T helper cell differentiation. Eur. J. Immunol. 34, 3604–3613 (2004).

    Article  CAS  PubMed  Google Scholar 

  116. Sekimata, M. et al. CCCTC-binding factor and the transcription factor T-bet orchestrate T helper 1 cell-specific structure and function at the interferon-γ locus. Immunity 31, 551–564 (2009). This study shows that CTCF and the TH1 cell-specific transcription factor T-bet shape local 3D chromatin folding required for proper inflammatory cytokine gene expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Hadjur, S. et al. Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus. Nature 460, 410–413 (2009). This work is the first study to show the functional role of cohesin in scaffolding long-range gene regulatory interactions at a developmentally regulated inflammatory cytokine gene locus.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Liu, C. F. et al. Crystal structure of the DNA binding domain of the transcription factor T-bet suggests simultaneous recognition of distant genome sites. Proc. Natl Acad. Sci. USA 113, E6572–E6581 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Spilianakis, C. G., Lalioti, M. D., Town, T., Lee, G. R. & Flavell, R. A. Interchromosomal associations between alternatively expressed loci. Nature 435, 637–645 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Chen, Y. et al. DNA binding by GATA transcription factor suggests mechanisms of DNA looping and long-range gene regulation. Cell Rep. 2, 1197–1206 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Hwang, S. S. et al. Transcription factor YY1 is essential for regulation of the TH2 cytokine locus and for TH2 cell differentiation. Proc. Natl Acad. Sci. USA 110, 276–281 (2013).

    Article  CAS  PubMed  Google Scholar 

  122. Cai, S., Lee, C. C. & Kohwi-Shigematsu, T. SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes. Nat. Genet. 38, 1278–1288 (2006).

    Article  CAS  PubMed  Google Scholar 

  123. Ribeiro de Almeida, C. et al. Critical role for the transcription regulator CCCTC-binding factor in the control of TH2 cytokine expression. J. Immunol. 182, 999–1010 (2009).

    Article  CAS  PubMed  Google Scholar 

  124. Ren, G. et al. CTCF-mediated enhancer–promoter interaction is a critical regulator of cell-to-cell variation of gene expression. Mol. Cell 67, 1049–1058.e6 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Johanson, T. M. et al. Genome-wide analysis reveals no evidence of trans chromosomal regulation of mammalian immune development. PLoS Genet. 14, e1007431 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Hakim, O. et al. Spatial congregation of STAT binding directs selective nuclear architecture during T-cell functional differentiation. Genome Res. 23, 462 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Li, P. et al. STAT5-mediated chromatin interactions in superenhancers activate IL-2 highly inducible genes: functional dissection of the Il2ra gene locus. Proc. Natl Acad. Sci. USA 114, 12111–12119 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Zhao, Y. et al. A new role for STAT3 as a regulator of chromatin topology. Transcription 4, 227–231 (2013).

    Article  PubMed  Google Scholar 

  129. Park, J.-H. et al. Dynamic long-range chromatin interaction controls expression of IL-21 in CD4+ T cells. J. Immunol. 196, 4378–4389 (2016).

    Article  CAS  PubMed  Google Scholar 

  130. Schwartz, D. M. et al. Retinoic acid receptor alpha represses a Th9 transcriptional and epigenomic program to reduce allergic pathology. Immunity 50, 106–120.e10 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Pham, D. et al. Batf pioneers the reorganization of chromatin in developing effector T cells via Ets1-dependent recruitment of Ctcf. Cell Rep. 29, 1203–1220.e7 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Doane, A. S. et al. OCT2 pre-positioning facilitates cell fate transition and chromatin architecture changes in humoral immunity. Nat. Immunol. 22, 1327–1340 (2021).

    Article  CAS  PubMed  Google Scholar 

  133. Bunting, K. L. et al. Multi-tiered reorganization of the genome during B cell affinity maturation anchored by a germinal center-specific locus control region. Immunity 45, 497–512 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Chaudhri, V. K., Dienger-Stambaugh, K., Wu, Z., Shrestha, M. & Singh, H. Charting the cis-regulome of activated B cells by coupling structural and functional genomics. Nat. Immunol. 21, 210–220 (2020).

    Article  CAS  PubMed  Google Scholar 

  135. Bortnick, A. et al. Plasma cell fate is orchestrated by elaborate changes in genome compartmentalization and inter-chromosomal hubs. Cell Rep. 31, 107470 (2020).

    Article  CAS  PubMed  Google Scholar 

  136. Chan, W. F. et al. Pre-mitotic genome re-organisation bookends the B cell differentiation process. Nat. Commun. 12, 1–13 (2021). This report reveals that 3D genome dynamics during mouse B cell activation occurs prior to DNA replication and mitosis, providing insights into how lymphocyte fate is imprinted prior to cell division.

    Article  CAS  Google Scholar 

  137. Chu, C. S. et al. Unique immune cell coactivators specify locus control region function and cell stage. Mol. Cell 80, 845–861.e10 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Hammad, H. & Lambrecht, B. N. The basic immunology of asthma. Cell 184, 1469–1485 (2021).

    Article  CAS  PubMed  Google Scholar 

  139. Bal, S. M., Golebski, K. & Spits, H. Plasticity of innate lymphoid cell subsets. Nat. Rev. Immunol. 20, 552–565 (2020).

    Article  CAS  PubMed  Google Scholar 

  140. Thommen, D. S. & Schumacher, T. N. T cell dysfunction in cancer. Cancer Cell 33, 547–562 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Feinberg, A. P. The key role of epigenetics in human disease prevention and mitigation. N. Engl. J. Med. 378, 1323–1334 (2018).

    Article  CAS  PubMed  Google Scholar 

  142. Schmiedel, B. J. et al. 17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells. Nat. Commun. 7, 13426 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Catrysse, L., Vereecke, L., Beyaert, R. & van Loo, G. A20 in inflammation and autoimmunity. Trends Immunol. 35, 22–31 (2014).

    Article  CAS  PubMed  Google Scholar 

  144. Wang, S., Wen, F., Wiley, G. B., Kinter, M. T. & Gaffney, P. M. An enhancer element harboring variants associated with systemic lupus erythematosus engages the TNFAIP3 promoter to influence A20 expression. PLoS Genet. 9, e1003750 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Bourges, C. et al. Resolving mechanisms of immune-mediated disease in primary CD4 T cells. EMBO Mol. Med. 12, e12112 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Calderon, D. et al. Landscape of stimulation-responsive chromatin across diverse human immune cells. Nat. Genet. 51, 1494–1505 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Watt, S. et al. Genetic perturbation of PU.1 binding and chromatin looping at neutrophil enhancers associates with autoimmune disease. Nat. Commun. 12, 1–12 (2021).

    Article  CAS  Google Scholar 

  148. Fasolino, M. et al. Genetic variation in type 1 diabetes reconfigures the 3D chromatin organization of T cells and alters gene expression. Immunity 52, 257–274.e11 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Ramirez, R. N., Chowdhary, K., Leon, J., Mathis, D. & Benoist, C. FoxP3 associates with enhancer–promoter loops to regulate Treg-specific gene expression. Sci. Immunol. 7, eabj9836 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Van Gool, F. et al. A mutation in the transcription factor Foxp3 drives T helper 2 effector function in regulatory T cells. Immunity 50, 362–377.e6 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Akdemir, K. C. et al. Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer. Nat. Genet. 52, 294–305 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Hnisz, D. et al. Activation of proto-oncogenes by disruption of chromosome neighborhoods. Science 351, 1454–1458 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Yang, M. et al. 13q12.2 deletions in acute lymphoblastic leukemia lead to upregulation of FLT3 through enhancer hijacking. Blood 136, 946–956 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Yang, H. et al. Noncoding genetic variation in GATA3 increases acute lymphoblastic leukemia risk through local and global changes in chromatin conformation. Nat. Genet. 54, 170–179 (2022).

    Article  CAS  PubMed  Google Scholar 

  155. Llimos, G. et al. A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation. Nat. Commun. 13, 1–21 (2022).

    Article  CAS  Google Scholar 

  156. Bhagwat, A. S., Lu, B. & Vakoc, C. R. Enhancer dysfunction in leukemia. Blood 131, 1795–1804 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Gröschel, S. et al. A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. Cell 157, 369–381 (2014).

    Article  PubMed  CAS  Google Scholar 

  158. Kloetgen, A. et al. Three-dimensional chromatin landscapes in T cell acute lymphoblastic leukemia. Nat. Genet. 52, 388–400 (2020). This paper describes widespread alterations in TAD insulation in T-ALL, including a TAD fusion event leading to aberrant Myc oncogene expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Fang, C. et al. Cancer-specific CTCF binding facilitates oncogenic transcriptional dysregulation. Genome Biol. 21, 247 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Lhoumaud, P. et al. NSD2 overexpression drives clustered chromatin and transcriptional changes in a subset of insulated domains. Nat. Commun. 10, 1–18 (2019).

    Article  CAS  Google Scholar 

  161. Flavahan, W. A. et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529, 110–114 (2016).

    Article  CAS  PubMed  Google Scholar 

  162. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368, 2059–2074 (2013).

    Article  CAS  Google Scholar 

  163. Luo, H. et al. HOTTIP-dependent R-loop formation regulates CTCF boundary activity and TAD integrity in leukemia. Mol. Cell 82, 833–851.e11 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Díaz, N. et al. Chromatin conformation analysis of primary patient tissue using a low input Hi-C method. Nat. Commun. 9, 1–13 (2018).

    Article  CAS  Google Scholar 

  165. Wu, P. et al. 3D genome of multiple myeloma reveals spatial genome disorganization associated with copy number variations. Nat. Commun. 8, 1937 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. Thota, S. et al. Genetic alterations of the cohesin complex genes in myeloid malignancies. Blood 124, 1790–1798 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Thol, F. et al. Mutations in the cohesin complex in acute myeloid leukemia: clinical and prognostic implications. Blood 123, 914–920 (2014).

    Article  CAS  PubMed  Google Scholar 

  168. Mullenders, J. et al. Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms. J. Exp. Med. 212, 1833–1850 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Mazumdar, C. et al. Leukemia-associated cohesin mutants dominantly enforce stem cell programs and impair human hematopoietic progenitor differentiation. Cell Stem Cell 17, 675–688 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Fisher, J. B. et al. The cohesin subunit Rad21 is a negative regulator of hematopoietic self-renewal through epigenetic repression of Hoxa7 and Hoxa9. Leukemia 31, 712–719 (2017).

    Article  CAS  PubMed  Google Scholar 

  171. Galeev, R. et al. Genome-wide RNAi screen identifies cohesin genes as modifiers of renewal and differentiation in human HSCs. Cell Rep. 14, 2988–3000 (2016).

    Article  CAS  PubMed  Google Scholar 

  172. Viny, A. D. et al. Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis. J. Exp. Med. 212, 1819–1832 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Oreskovic, E. et al. Genetic analysis of cancer drivers reveals cohesin and CTCF as suppressors of PD-L1. Proc. Natl Acad. Sci. USA 119, e2120540119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Pietras, E. M. Inflammation: a key regulator of hematopoietic stem cell fate in health and disease. Blood 130, 1693–1698 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Viny, A. D. et al. Cohesin members Stag1 and Stag2 display distinct roles in chromatin accessibility and topological control of HSC self-renewal and differentiation. Cell Stem Cell 25, 682–696.e8 (2019). This study elegantly dissects the role of Stag1 and Stag2 in haematopoiesis and shows that Stag2 is essential for B cell differentiation by promoting local chromatin interactions at the Ebf1 gene locus.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Rivas, M. A. et al. Smc3 dosage regulates B cell transit through germinal centers and restricts their malignant transformation. Nat. Immunol. 22, 240–253 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Yang, M. et al. Proteogenomics and Hi-C reveal transcriptional dysregulation in high hyperdiploid childhood acute lymphoblastic leukemia. Nat. Commun. 10, 1–15 (2019).

    CAS  Google Scholar 

  178. Steidl, U. et al. A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia. J. Clin. Invest. 117, 2611 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Harro, C. M. et al. Methyltransferase inhibitors restore SATB1 protective activity against cutaneous T cell lymphoma in mice. J. Clin. Invest 131, e135711 (2021).

    Article  CAS  PubMed Central  Google Scholar 

  180. Naik, R. & Galande, S. SATB family chromatin organizers as master regulators of tumor progression. Oncogene 38, 1989–2004 (2018).

    Article  PubMed  CAS  Google Scholar 

  181. Donaldson-Collier, M. C. et al. EZH2 oncogenic mutations drive epigenetic, transcriptional, and structural changes within chromatin domains. Nat. Genet. 51, 517–528 (2019). This study describes how EZH2 mutations in lymphoma drive transcriptional repression in a TAD-concordant manner, inactivating entire TADs containing multiple tumour-suppressor genes.

    Article  CAS  PubMed  Google Scholar 

  182. Reilly, A. et al. Lamin B1 deletion in myeloid neoplasms causes nuclear anomaly and altered hematopoietic stem cell function. Cell Stem Cell https://doi.org/10.1016/j.stem.2022.02.010 (2022).

    Article  PubMed  Google Scholar 

  183. Petrovic, J. et al. Oncogenic notch promotes long-range regulatory interactions within hyperconnected 3D cliques. Mol. Cell 73, 1174–1190.e12 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Antoszewski, M. et al. Tcf1 is essential for initiation of oncogenic Notch1-driven chromatin topology in T-ALL. Blood 139, 2483–2498 (2022).

    Article  CAS  PubMed  Google Scholar 

  185. Zhou, Y. et al. EBF1 nuclear repositioning instructs chromatin refolding to promote therapy resistance in T leukemic cells. Mol. Cell 82, 1003–1020.e15 (2022).

    Article  CAS  PubMed  Google Scholar 

  186. Ahn, J. H. et al. Phase separation drives aberrant chromatin looping and cancer development. Nature 595, 591–595 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. McSwiggen, D. T., Mir, M., Darzacq, X. & Tjian, R. Evaluating phase separation in live cells: diagnosis, caveats, and functional consequences. Genes Dev. 33, 1619–1634 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Beagan, J. A. & Phillips-Cremins, J. E. On the existence and functionality of topologically associating domains. Nat. Genet. 52, 8–16 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Cavalheiro, G. R., Pollex, T. & Furlong, E. E. To loop or not to loop: what is the role of TADs in enhancer function and gene regulation? Curr. Opin. Genet. Dev. 67, 119–129 (2021).

    Article  CAS  PubMed  Google Scholar 

  190. Zuin, J. et al. Nonlinear control of transcription through enhancer–promoter interactions. Nature 604, 571–577 (2022). This study convincingly shows that transcriptional activation by an enhancer depends on its genomic distance from the promoter through a non-linear relationship with their contact probabilities.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. He, B. et al. CD8+ T cells utilize highly dynamic enhancer repertoire and regulatory circuitries in response to infections. Immunity 45, 1341 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Bevington, S. L. et al. Inducible chromatin priming is associated with the establishment of immunological memory in T cells. EMBO J. 35, 515–535 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Shan, Q. et al. Tcf1 preprograms the mobilization of glycolysis in central memory CD8+ T cells during recall responses. Nat. Immunol. 23, 386–398 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Papalexi, E. & Satija, R. Single-cell RNA sequencing to explore immune cell heterogeneity. Nat. Rev. Immunol. 18, 35–45 (2018).

    Article  CAS  PubMed  Google Scholar 

  195. Ginhoux, F., Yalin, A., Dutertre, C. A. & Amit, I. Single-cell immunology: past, present, and future. Immunity 55, 393–404 (2022).

    Article  CAS  PubMed  Google Scholar 

  196. Finn, E. H. & Misteli, T. A genome disconnect. Nat. Genet. 51, 1205–1206 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Harewood, L. & Fraser, P. The impact of chromosomal rearrangements on regulation of gene expression. Hum. Mol. Genet. 23, ddu278 (2014).

    Article  CAS  Google Scholar 

  198. Dixon, J. R. et al. Integrative detection and analysis of structural variation in cancer genomes. Nat. Genet. 50, 1388–1398 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Chandra, V. et al. Promoter-interacting expression quantitative trait loci are enriched for functional genetic variants. Nat. Genet. 53, 110–119 (2021).

    Article  CAS  PubMed  Google Scholar 

  200. Hua, P. et al. Defining genome architecture at base-pair resolution. Nature 595, 125–129 (2021).

    Article  CAS  PubMed  Google Scholar 

  201. van Schoonhoven, A. & Stadhouders, R. A base-pair view of interactions between genes and their enhancers. Nature 595, 36–37 (2021).

    Article  PubMed  CAS  Google Scholar 

  202. de Wit, E. & de Laat, W. A decade of 3C technologies: insights into nuclear organization. Genes Dev. 26, 11–24 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  203. Kempfer, R. & Pombo, A. Methods for mapping 3D chromosome architecture. Nat. Rev. Genet. 21, 207–226 (2020).

    Article  CAS  PubMed  Google Scholar 

  204. de Almeida, C. R., Hendriks, R. W. & Stadhouders, R. Dynamic control of long-range genomic interactions at the immunoglobulin κ light-chain locus. Adv. Immunol. 128, 183–271 (2015).

    Article  CAS  Google Scholar 

  205. Proudhon, C., Hao, B., Raviram, R., Chaumeil, J. & Skok, J. A. Long-range regulation of V(D)J recombination. Adv. Immunol. 128, 123–182 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Schatz, D. G. & Ji, Y. Recombination centres and the orchestration of V(D)J recombination. Nat. Rev. Immunol. 11, 251–263 (2011).

    Article  CAS  PubMed  Google Scholar 

  207. Bossen, C., Mansson, R. & Murre, C. Chromatin topology and the regulation of antigen receptor assembly. Annu. Rev. Immunol. 30, 337–356 (2012).

    Article  CAS  PubMed  Google Scholar 

  208. Zhang, Y., Zhang, X., Dai, H. Q., Hu, H. & Alt, F. W. The role of chromatin loop extrusion in antibody diversification. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-022-00679-3 (2022).

    Article  PubMed  Google Scholar 

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Acknowledgements

S.C. is supported by a ‘La Caixa’ Junior Leader fellowship (LCF/BQ/PI20/11760002), the Jérôme Lejeune Foundation (JLF #1902) and the Spanish Ministry of Science and Innovation (PID2020-117950RA-I00). G.S. is supported by the ‘Fundación Científica de la Asociación Española Contra el Cáncer’. R.S. is supported by an Erasmus MC Fellowship, a Dutch Lung Foundation Junior Investigator grant (4.2.19.041JO), a Daniel den Hoed Foundation grant and an NWO Vidi grant (09150172010068). The authors acknowledge support by the Spanish Ministry of Science and Innovation, to the EMBL partnership, the Centro de Excelencia Severo Ochoa, the Josep Carreras Foundation and the CERCA Programme/Generalitat de Catalunya.

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Cuartero, S., Stik, G. & Stadhouders, R. Three-dimensional genome organization in immune cell fate and function. Nat Rev Immunol (2022). https://doi.org/10.1038/s41577-022-00774-5

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