Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Biomolecular condensates in immune cell fate

Abstract

Fate decisions during immune cell development require temporally precise changes in gene expression. Evidence suggests that the dynamic modulation of these changes is associated with the formation of diverse, membrane-less nucleoprotein assemblies that are termed biomolecular condensates. These condensates are thought to orchestrate fate-determining transcriptional and post-transcriptional processes by locally and transiently concentrating DNA or RNA molecules alongside their regulatory proteins. Findings have established a link between condensate formation and the gene regulatory networks that ensure the proper development of immune cells. Conversely, condensate dysregulation has been linked to impaired immune cell fates, including ageing and malignant transformation. This Review explores the putative mechanistic links between condensate assembly and the gene regulatory frameworks that govern normal and pathological development in the immune system.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Biomolecular condensates in gene regulation.
Fig. 2: Biomolecular condensates are linked to normal immune cell fates.
Fig. 3: Biomolecular condensate dysregulation is linked to pathological immune cell fates.
Fig. 4: Technologies to analyse biomolecular condensate composition.

Similar content being viewed by others

References

  1. Flajnik, M. F. & Kasahara, M. Origin and evolution of the adaptive immune system: genetic events and selective pressures. Nat. Rev. Genet. 11, 47–59 (2010).

    Article  CAS  PubMed  Google Scholar 

  2. Litman, G. W., Rast, J. P. & Fugmann, S. D. The origins of vertebrate adaptive immunity. Nat. Rev. Immunol. 10, 543–553 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Carpenter, S. & O’Neill, L. A. J. From periphery to center stage: 50 years of advancements in innate immunity. Cell 187, 2030–2051 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chi, H., Pepper, M. & Thomas, P. G. Principles and therapeutic applications of adaptive immunity. Cell 187, 2052–2078 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pinho, S. & Frenette, P. S. Haematopoietic stem cell activity and interactions with the niche. Nat. Rev. Mol. Cell Biol. 20, 303–320 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Orkin, S. H. & Zon, L. I. Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132, 631–644 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wilkinson, A. C., Igarashi, K. J. & Nakauchi, H. Haematopoietic stem cell self-renewal in vivo and ex vivo. Nat. Rev. Genet. 21, 541–554 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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 

  9. Chua, B. A., Van Der Werf, I., Jamieson, C. & Signer, R. A. J. Post-transcriptional regulation of homeostatic, stressed, and malignant stem cells. Cell Stem Cell 26, 138–159 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Raj, A. & van Oudenaarden, A. Nature, nurture, or chance: stochastic gene expression and its consequences. Cell 135, 216–226 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sabari, B. R. Biomolecular condensates and gene activation in development and disease. Dev. Cell 55, 84–96 (2020).

    Article  CAS  PubMed  Google Scholar 

  12. Banani, S. F., Lee, H. O., Hyman, A. A. & Rosen, M. K. Biomolecular condensates: organizers of cellular biochemistry. Nat. Rev. Mol. Cell Biol. 18, 285–298 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Li, P. et al. High-throughput and proteome-wide discovery of endogenous biomolecular condensates. Nat. Chem. 16, 1101–1112 (2024).

    Article  CAS  PubMed  Google Scholar 

  14. Gorsheneva, N. A., Sopova, J. V., Azarov, V. V., Grizel, A. V. & Rubel, A. A. Biomolecular condensates: structure, functions, methods of research. Biochemistry 89, S205–S223 (2024).

    CAS  PubMed  Google Scholar 

  15. Zacco, E. et al. RNA: the unsuspected conductor in the orchestra of macromolecular crowding. Chem. Rev. 124, 4734–4777 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wadsworth, G. M. et al. RNA-driven phase transitions in biomolecular condensates. Mol. Cell 84, 3692–3705 (2024).

    Article  CAS  PubMed  Google Scholar 

  17. Roden, C. & Gladfelter, A. S. RNA contributions to the form and function of biomolecular condensates. Nat. Rev. Mol. Cell Biol. 22, 183–195 (2021).

    Article  CAS  PubMed  Google Scholar 

  18. Cech, T. R. RNA in biological condensates. RNA 28, 1–2 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Rangachari, V. Biomolecular condensates — extant relics or evolving microcompartments? Commun. Biol. 6, 656 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mitrea, D. M., Mittasch, M., Gomes, B. F., Klein, I. A. & Murcko, M. A. Modulating biomolecular condensates: a novel approach to drug discovery. Nat. Rev. Drug. Discov. 21, 841–862 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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 

  22. Sharp, P. A., Chakraborty, A. K., Henninger, J. E. & Young, R. A. RNA in formation and regulation of transcriptional condensates. RNA 28, 52–57 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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 

  24. Du, M. et al. Direct observation of a condensate effect on super-enhancer controlled gene bursting. Cell 187, 331–344.e317 (2024).

    Article  CAS  PubMed  Google Scholar 

  25. Sabari, B. R. et al. Coactivator condensation at super-enhancers links phase separation and gene control. Science 361, eaar3958 (2018). This study provides experimental evidence that components of the transcriptional machinery, specifically BRD4 and MED1, can form condensates at super-enhancer-regulated genes.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Kilgore, H. R. et al. Distinct chemical environments in biomolecular condensates. Nat. Chem. Biol. 20, 291–301 (2024).

    Article  CAS  PubMed  Google Scholar 

  27. Lyons, H. et al. Functional partitioning of transcriptional regulators by patterned charge blocks. Cell 186, 327–345.e328 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cisse, I. I. et al. Real-time dynamics of RNA polymerase II clustering in live human cells. Science 341, 664–667 (2013).

    Article  CAS  PubMed  Google Scholar 

  29. Cho, W. K. et al. Mediator and RNA polymerase II clusters associate in transcription-dependent condensates. Science 361, 412–415 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ryu, K., Park, G. & Cho, W. K. Emerging insights into transcriptional condensates. Exp. Mol. Med. 56, 820–826 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Brodsky, S., Jana, T. & Barkai, N. Order through disorder: the role of intrinsically disordered regions in transcription factor binding specificity. Curr. Opin. Struct. Biol. 71, 110–115 (2021).

    Article  CAS  PubMed  Google Scholar 

  32. Brodsky, S. et al. Intrinsically disordered regions direct transcription factor in vivo binding specificity. Mol. Cell 79, 459–471.e454 (2020).

    Article  CAS  PubMed  Google Scholar 

  33. Boija, A. et al. Transcription factors activate genes through the phase-separation capacity of their activation domains. Cell 175, 1842–1855.e1816 (2018).

    Article  CAS  PubMed  Google Scholar 

  34. Lavering, E. D., Gandhamaneni, M. & Weeks, D. L. Intrinsically disordered regions are not sufficient to direct the compartmental localization of nucleolar proteins in the nucleus. PLoS Biol. 21, e3002378 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  35. He, J. et al. Dual-role transcription factors stabilize intermediate expression levels. Cell 187, 2746–2766.e2725 (2024).

    Article  CAS  PubMed  Google Scholar 

  36. Cho, W. K. et al. RNA polymerase II cluster dynamics predict mRNA output in living cells. Elife 5, e13617 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Ilik, I. A. & Aktas, T. Nuclear speckles: dynamic hubs of gene expression regulation. FEBS J. 289, 7234–7245 (2022).

    Article  CAS  PubMed  Google Scholar 

  38. Chen, Y. & Belmont, A. S. Genome organization around nuclear speckles. Curr. Opin. Genet. Dev. 55, 91–99 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Spector, D. L. & Lamond, A. I. Nuclear speckles. Cold Spring Harb. Perspect. Biol. 3, a000646 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Giudice, J. & Jiang, H. Splicing regulation through biomolecular condensates and membraneless organelles. Nat. Rev. Mol. Cell Biol. 25, 683–700 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Carter, K. C., Taneja, K. L. & Lawrence, J. B. Discrete nuclear domains of poly(A) RNA and their relationship to the functional organization of the nucleus. J. Cell Biol. 115, 1191–1202 (1991).

    Article  CAS  PubMed  Google Scholar 

  42. Bhat, P. et al. Genome organization around nuclear speckles drives mRNA splicing efficiency. Nature 629, 1165–1173 (2024). This work uncovers a functional role for nuclear speckles in splicing, showing that spatial organization of actively transcribed genes near speckles boosts splicing efficiency of their pre-mRNAs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kim, J., Venkata, N. C., Hernandez Gonzalez, G. A., Khanna, N. & Belmont, A. S. Gene expression amplification by nuclear speckle association. J. Cell Biol. 219, e201904046 (2020).

    PubMed  Google Scholar 

  44. Alexander, K. A. et al. p53 mediates target gene association with nuclear speckles for amplified RNA expression. Mol. Cell 81, 1666–1681.e1666 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chan, S. P. & Slack, F. J. microRNA-mediated silencing inside P-bodies. RNA Biol. 3, 97–100 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Decker, C. J. & Parker, R. P-bodies and stress granules: possible roles in the control of translation and mRNA degradation. Cold Spring Harb. Perspect. Biol. 4, a012286 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Eulalio, A., Behm-Ansmant, I. & Izaurralde, E. P bodies: at the crossroads of post-transcriptional pathways. Nat. Rev. Mol. Cell. Biol. 8, 9–22 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Kulkarni, M., Ozgur, S. & Stoecklin, G. On track with P-bodies. Biochem. Soc. Trans. 38, 242–251 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. Luo, Y., Na, Z. & Slavoff, S. A. P-bodies: composition, properties, and functions. Biochemistry 57, 2424–2431 (2018).

    Article  CAS  PubMed  Google Scholar 

  50. Parker, R. & Sheth, U. P bodies and the control of mRNA translation and degradation. Mol. Cell 25, 635–646 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Riggs, C. L., Kedersha, N., Ivanov, P. & Anderson, P. Mammalian stress granules and P bodies at a glance. J. Cell Sci. 133, jcs242487 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Standart, N. & Weil, D. P-bodies: cytosolic droplets for coordinated mRNA storage. Trends Genet. 34, 612–626 (2018).

    Article  CAS  PubMed  Google Scholar 

  53. Freimer, J. W., Hu, T. J. & Blelloch, R. Decoupling the impact of microRNAs on translational repression versus RNA degradation in embryonic stem cells. Elife 7, e38014 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Buchan, J. R. mRNP granules. Assembly, function, and connections with disease. RNA Biol. 11, 1019–1030 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Wang, C. et al. Context-dependent deposition and regulation of mRNAs in P-bodies. Elife 7, e29815 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Mathys, H. et al. Structural and biochemical insights to the role of the CCR4–NOT complex and DDX6 ATPase in microRNA repression. Mol. Cell 54, 751–765 (2014).

    Article  CAS  PubMed  Google Scholar 

  57. Cardona, A. H. et al. Self-demixing of mRNA copies buffers mRNA:mRNA and mRNA:regulator stoichiometries. Cell 186, 4310–4324.e4323 (2023). This study demonstrates how RNA condensates, specifically P-bodies, can robustly and selectively buffer translationally repressed mRNAs and counters the notion that P-bodies have limited storage capacity.

    Article  CAS  PubMed  Google Scholar 

  58. Brothers, W. R., Ali, F., Kajjo, S. & Fabian, M. R. The EDC4–XRN1 interaction controls P-body dynamics to link mRNA decapping with decay. EMBO J. 42, e113933 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Blake, L. A., Watkins, L., Liu, Y., Inoue, T. & Wu, B. A rapid inducible RNA decay system reveals fast mRNA decay in P-bodies. Nat. Commun. 15, 2720 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Millar, S. R. et al. A new phase of networking: the molecular composition and regulatory dynamics of mammalian stress granules. Chem. Rev. 123, 9036–9064 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Protter, D. S. W. & Parker, R. Principles and properties of stress granules. Trends Cell Biol. 26, 668–679 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Redding, A. & Grabocka, E. Stress granules and hormetic adaptation of cancer. Trends Cancer 9, 995–1005 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Riback, J. A. et al. Stress-triggered phase separation is an adaptive, evolutionarily tuned response. Cell 168, 1028–1040.e1019 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hofmann, S., Kedersha, N., Anderson, P. & Ivanov, P. Molecular mechanisms of stress granule assembly and disassembly. Biochim. Biophys. Acta Mol. Cell Res. 1868, 118876 (2021).

    Article  CAS  PubMed  Google Scholar 

  65. Ries, R. J., Pickering, B. F., Poh, H. X., Namkoong, S. & Jaffrey, S. R. m6A governs length-dependent enrichment of mRNAs in stress granules. Nat. Struct. Mol. Biol. 30, 1525–1535 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Park, J. et al. Poly(GR) interacts with key stress granule factors promoting its assembly into cytoplasmic inclusions. Cell Rep. 42, 112822 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ries, R. J. et al. m6A enhances the phase separation potential of mRNA. Nature 571, 424–428 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Khong, A., Matheny, T., Huynh, T. N., Babl, V. & Parker, R. Limited effects of m6A modification on mRNA partitioning into stress granules. Nat. Commun. 13, 3735 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Pelletier, J., Thomas, G. & Volarevic, S. Ribosome biogenesis in cancer: new players and therapeutic avenues. Nat. Rev. Cancer 18, 51–63 (2018).

    Article  CAS  PubMed  Google Scholar 

  70. Lafontaine, D. L. J., Riback, J. A., Bascetin, R. & Brangwynne, C. P. The nucleolus as a multiphase liquid condensate. Nat. Rev. Mol. Cell Biol. 22, 165–182 (2021).

    Article  CAS  PubMed  Google Scholar 

  71. Mensah, M. A. et al. Aberrant phase separation and nucleolar dysfunction in rare genetic diseases. Nature 614, 564–571 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Corman, A., Sirozh, O., Lafarga, V. & Fernandez-Capetillo, O. Targeting the nucleolus as a therapeutic strategy in human disease. Trends Biochem. Sci. 48, 274–287 (2023).

    Article  CAS  PubMed  Google Scholar 

  73. Riback, J. A. et al. Composition-dependent thermodynamics of intracellular phase separation. Nature 581, 209–214 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Russell, J. & Zomerdijk, J. C. RNA-polymerase-I-directed rDNA transcription, life and works. Trends Biochem. Sci. 30, 87–96 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Bernardi, R. & Pandolfi, P. P. Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies. Nat. Rev. Mol. Cell Biol. 8, 1006–1016 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Lallemand-Breitenbach, V. & de The, H. PML nuclear bodies. Cold Spring Harb. Perspect. Biol. 2, a000661 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Boisvert, F. M., Hendzel, M. J. & Bazett-Jones, D. P. Promyelocytic leukemia (PML) nuclear bodies are protein structures that do not accumulate RNA. J. Cell Biol. 148, 283–292 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Vertegaal, A. C. O. Signalling mechanisms and cellular functions of SUMO. Nat. Rev. Mol. Cell Biol. 23, 715–731 (2022).

    Article  CAS  PubMed  Google Scholar 

  79. Shen, T. H., Lin, H. K., Scaglioni, P. P., Yung, T. M. & Pandolfi, P. P. The mechanisms of PML-nuclear body formation. Mol. Cell 24, 331–339 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Olson, O. C., Kang, Y. A. & Passegue, E. Normal hematopoiesis is a balancing act of self-renewal and regeneration. Cold Spring Harb. Perspect. Med. 10, a035519 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Li, Z. et al. Suppression of m6A reader Ythdf2 promotes hematopoietic stem cell expansion. Cell Res. 28, 904–917 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Cheng, Y. et al. m6A RNA methylation maintains hematopoietic stem cell identity and symmetric commitment. Cell Rep. 28, 1703–1716.e1706 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lee, H. et al. Stage-specific requirement for Mettl3-dependent m6A mRNA methylation during haematopoietic stem cell differentiation. Nat. Cell Biol. 21, 700–709 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Zhang, C. et al. m6A modulates haematopoietic stem and progenitor cell specification. Nature 549, 273–276 (2017).

    Article  CAS  PubMed  Google Scholar 

  85. Yao, Q. J. et al. Mettl3–Mettl14 methyltransferase complex regulates the quiescence of adult hematopoietic stem cells. Cell Res. 28, 952–954 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Gao, Y. et al. ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m6A modification-mediated RNA stability control. Cell Rep. 42, 113163 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Sharma, A., Takata, H., Shibahara, K., Bubulya, A. & Bubulya, P. A. Son is essential for nuclear speckle organization and cell cycle progression. Mol. Biol. Cell 21, 650–663 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Luo, H. et al. SON is an essential m6A target for hematopoietic stem cell fate. Cell Stem Cell 30, 1658–1673.e1610 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ilik, I. A. et al. SON and SRRM2 are essential for nuclear speckle formation. Elife 9, e60579 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lu, X. et al. SON connects the splicing-regulatory network with pluripotency in human embryonic stem cells. Nat. Cell Biol. 15, 1141–1152 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Signer, R. A., Magee, J. A., Salic, A. & Morrison, S. J. Haematopoietic stem cells require a highly regulated protein synthesis rate. Nature 509, 49–54 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Courel, M. et al. GC content shapes mRNA storage and decay in human cells. Elife 8, e49708 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Brengues, M., Teixeira, D. & Parker, R. Movement of eukaryotic mRNAs between polysomes and cytoplasmic processing bodies. Science 310, 486–489 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Di Stefano, B. et al. The RNA helicase DDX6 controls cellular plasticity by modulating P-body homeostasis. Cell Stem Cell 25, 622–638.e613 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Hubstenberger, A. et al. P-body purification reveals the condensation of repressed mRNA regulons. Mol. Cell 68, 144–157.e145 (2017).

    Article  CAS  PubMed  Google Scholar 

  96. Teixeira, D., Sheth, U., Valencia-Sanchez, M. A., Brengues, M. & Parker, R. Processing bodies require RNA for assembly and contain nontranslating mRNAs. RNA 11, 371–382 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Aizer, A. et al. Quantifying mRNA targeting to P-bodies in living human cells reveals their dual role in mRNA decay and storage. J. Cell Sci. 127, 4443–4456 (2014).

    CAS  PubMed  Google Scholar 

  98. Ayache, J. et al. P-body assembly requires DDX6 repression complexes rather than decay or Ataxin2/2L complexes. Mol. Biol. Cell 26, 2579–2595 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Kamenska, A. et al. The DDX6–4E-T interaction mediates translational repression and P-body assembly. Nucleic Acids Res. 44, 6318–6334 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kodali, S. et al. RNA sequestration in P-bodies sustains myeloid leukaemia. Nat. Cell Biol. 26, 1745–1758 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Schoedel, K. B. et al. The bulk of the hematopoietic stem cell population is dispensable for murine steady-state and stress hematopoiesis. Blood 128, 2285–2296 (2016).

    Article  CAS  PubMed  Google Scholar 

  102. Pietras, E. M. et al. Functionally distinct subsets of lineage-biased multipotent progenitors control blood production in normal and regenerative conditions. Cell Stem Cell 17, 35–46 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Pradeu, T., Thomma, B., Girardin, S. E. & Lemaitre, B. The conceptual foundations of innate immunity: taking stock 30 years later. Immunity 57, 613–631 (2024).

    Article  CAS  PubMed  Google Scholar 

  104. Okabe, Y. & Medzhitov, R. Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell 157, 832–844 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ochando, J., Mulder, W. J. M., Madsen, J. C., Netea, M. G. & Duivenvoorden, R. Trained immunity — basic concepts and contributions to immunopathology. Nat. Rev. Nephrol. 19, 23–37 (2023).

    Article  PubMed  Google Scholar 

  106. Akashi, K., Traver, D., Miyamoto, T. & Weissman, I. L. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404, 193–197 (2000).

    Article  CAS  PubMed  Google Scholar 

  107. Suh, H. C. et al. C/EBPα determines hematopoietic cell fate in multipotential progenitor cells by inhibiting erythroid differentiation and inducing myeloid differentiation. Blood 107, 4308–4316 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Xie, H., Ye, M., Feng, R. & Graf, T. Stepwise reprogramming of B cells into macrophages. Cell 117, 663–676 (2004).

    Article  CAS  PubMed  Google Scholar 

  109. Bussmann, L. H. et al. A robust and highly efficient immune cell reprogramming system. Cell Stem Cell 5, 554–566 (2009).

    Article  CAS  PubMed  Google Scholar 

  110. Christou-Kent, M. et al. CEBPA phase separation links transcriptional activity and 3D chromatin hubs. Cell Rep. 42, 112897 (2023). This work links the condensation ability of the crucial myeloid transcription factor C/EBPα to its ability to rewire chromatin organization and transcription.

    Article  CAS  PubMed  Google Scholar 

  111. Naderi, J. et al. An activity-specificity trade-off encoded in human transcription factors. Nat. Cell Biol. 26, 1309–1321 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Lawrence, T. & Natoli, G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat. Rev. Immunol. 11, 750–761 (2011).

    Article  CAS  PubMed  Google Scholar 

  113. Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 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 

  115. Jia, P. et al. ZMYND8 mediated liquid condensates spatiotemporally decommission the latent super-enhancers during macrophage polarization. Nat. Commun. 12, 6535 (2021). This study shows how condensate formation by the chromatin reader ZMYND8 acts as a brake on de novo super-enhancer activity in polarized macrophages to limit inflammation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Kondo, M. Lymphoid and myeloid lineage commitment in multipotent hematopoietic progenitors. Immunol. Rev. 238, 37–46 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Lin, H. & Grosschedl, R. Failure of B-cell differentiation in mice lacking the transcription factor EBF. Nature 376, 263–267 (1995).

    Article  CAS  PubMed  Google Scholar 

  118. Morgan, D. & Tergaonkar, V. Unraveling B cell trajectories at single cell resolution. Trends Immunol. 43, 210–229 (2022).

    Article  CAS  PubMed  Google Scholar 

  119. Wang, Y. et al. A prion-like ___domain in transcription factor EBF1 promotes phase separation and enables B cell programming of progenitor chromatin. Immunity 53, 1151–1167.e1156 (2020). This work links transcriptional condensates to B cell differentiation, showing that the intrinsically disordered ___domain of the transcription factor EBF1 enables it to open closed chromatin at B cell fate-instructive genes.

    Article  CAS  PubMed  Google Scholar 

  120. Boller, S. et al. Pioneering activity of the C-terminal ___domain of EBF1 shapes the chromatin landscape for B cell programming. Immunity 44, 527–541 (2016).

    Article  CAS  PubMed  Google Scholar 

  121. Ravindran, R. & Michnick, S. W. Biomolecular condensates as drivers of membrane trafficking and remodelling. Curr. Opin. Cell Biol. 89, 102393 (2024).

    Article  CAS  PubMed  Google Scholar 

  122. Akkaya, M., Kwak, K. & Pierce, S. K. B cell memory: building two walls of protection against pathogens. Nat. Rev. Immunol. 20, 229–238 (2020).

    Article  CAS  PubMed  Google Scholar 

  123. Cyster, J. G. & Allen, C. D. C. B cell responses: cell interaction dynamics and decisions. Cell 177, 524–540 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Kastenhuber, E. R. & Lowe, S. W. Putting p53 in context. Cell 170, 1062–1078 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Diaz-Munoz, M. D. et al. Tia1 dependent regulation of mRNA subcellular ___location and translation controls p53 expression in B cells. Nat. Commun. 8, 530 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Gilks, N. et al. Stress granule assembly is mediated by prion-like aggregation of TIA-1. Mol. Biol. Cell 15, 5383–5398 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Curdy, N. et al. The proteome and transcriptome of stress granules and P bodies during human T lymphocyte activation. Cell Rep. 42, 112211 (2023).

    Article  CAS  PubMed  Google Scholar 

  128. Glasmacher, E. et al. Roquin binds inducible costimulator mRNA and effectors of mRNA decay to induce microRNA-independent post-transcriptional repression. Nat. Immunol. 11, 725–733 (2010). This work establishes a link between localization of specific transcripts within condensates and autoimmunity, showing that the RNA-binding protein Roquin1 must localize to P-bodies to repress transcripts that encode ICOS, which is a driver of T cell activation.

    Article  CAS  PubMed  Google Scholar 

  129. Zuniga-Pflucker, J. C. T-cell development made simple. Nat. Rev. Immunol. 4, 67–72 (2004).

    Article  CAS  PubMed  Google Scholar 

  130. 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 

  131. Johnson, J. L. et al. Lineage-determining transcription factor TCF-1 initiates the epigenetic identity of T cells. Immunity 48, 243–257.e210 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Gounari, F. & Khazaie, K. TCF-1: a maverick in T cell development and function. Nat. Immunol. 23, 671–678 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Goldman, N. et al. Intrinsically disordered ___domain of transcription factor TCF-1 is required for T cell developmental fidelity. Nat. Immunol. 24, 1698–1710 (2023). This study implicates transcriptional condensates in early T cell development, showing that the intrinsically disordered region of the transcription factor TCF-1 is required to enforce T cell lineage commitment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Kunzli, M. & Masopust, D. CD4+ T cell memory. Nat. Immunol. 24, 903–914 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Chapman, N. M., Boothby, M. R. & Chi, H. Metabolic coordination of T cell quiescence and activation. Nat. Rev. Immunol. 20, 55–70 (2020).

    Article  CAS  PubMed  Google Scholar 

  136. Zhou, L. et al. T cell proliferation requires ribosomal maturation in nucleolar condensates dependent on DCAF13. J. Cell Biol. 222, e202201096 (2023). This work examines the role of nucleolar organization in T cell activation, providing evidence that the nucleolar protein DCAF13 promotes condensation of the ribosomal assembly machinery with ribosomal components.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Zhang, J. et al. Mammalian nucleolar protein DCAF13 is essential for ovarian follicle maintenance and oocyte growth by mediating rRNA processing. Cell Death Differ. 26, 1251–1266 (2019).

    Article  CAS  PubMed  Google Scholar 

  138. Bleichert, F., Granneman, S., Osheim, Y. N., Beyer, A. L. & Baserga, S. J. The PINc ___domain protein Utp24, a putative nuclease, is required for the early cleavage steps in 18S rRNA maturation. Proc. Natl Acad. Sci. USA 103, 9464–9469 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Allan, R. S. et al. An epigenetic silencing pathway controlling T helper 2 cell lineage commitment. Nature 487, 249–253 (2012).

    Article  CAS  PubMed  Google Scholar 

  140. Allshire, R. C. & Madhani, H. D. Ten principles of heterochromatin formation and function. Nat. Rev. Mol. Cell Biol. 19, 229–244 (2018).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. 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 

  143. Tortora, M. M. C., Brennan, L. D., Karpen, G. & Jost, D. HP1-driven phase separation recapitulates the thermodynamics and kinetics of heterochromatin condensate formation. Proc. Natl Acad. Sci. USA 120, e2211855120 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Erdel, F. et al. Mouse heterochromatin adopts digital compaction states without showing hallmarks of HP1-driven liquid-liquid phase separation. Mol. Cell 78, 236–249.e237 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Tough, D. F., Rioja, I., Modis, L. K. & Prinjha, R. K. Epigenetic regulation of T cell memory: recalling therapeutic implications. Trends Immunol. 41, 29–45 (2020).

    Article  CAS  PubMed  Google Scholar 

  146. Cuartero, S., Stik, G. & Stadhouders, R. Three-dimensional genome organization in immune cell fate and function. Nat. Rev. Immunol. 23, 206–221 (2023).

    Article  CAS  PubMed  Google Scholar 

  147. Acemel, R. D. & Lupianez, D. G. Evolution of 3D chromatin organization at different scales. Curr. Opin. Genet. Dev. 78, 102019 (2023).

    Article  CAS  PubMed  Google Scholar 

  148. Zheng, H. & Xie, W. The role of 3D genome organization in development and cell differentiation. Nat. Rev. Mol. Cell Biol. 20, 535–550 (2019).

    Article  CAS  PubMed  Google Scholar 

  149. Onrust-van Schoonhoven, A. et al. 3D chromatin reprogramming primes human memory TH2 cells for rapid recall and pathogenic dysfunction. Sci. Immunol. 8, eadg3917 (2023). This study uncovers the compartmentalization of recall response genes and their regulatory elements in memory T cells, linking spatial organization of chromatin to immunological memory.

    Article  CAS  PubMed  Google Scholar 

  150. Crotty, S. T follicular helper cell differentiation, function, and roles in disease. Immunity 41, 529–542 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Vinuesa, C. G. et al. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435, 452–458 (2005).

    Article  CAS  PubMed  Google Scholar 

  152. Tavernier, S. J. et al. A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation. Nat. Commun. 10, 4779 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Ross, S. H. & Cantrell, D. A. Signaling and function of interleukin-2 in T lymphocytes. Annu. Rev. Immunol. 36, 411–433 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Spolski, R. et al. Distinct use of super-enhancer elements controls cell type-specific CD25 transcription and function. Sci. Immunol. 8, eadi8217 (2023). This study uncovers the differential use of super-enhancer elements to achieve cell type-specific expression patterns of a key cytokine receptor gene, CD25, in distinct T cell lineages.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Blayney, J. W. et al. Super-enhancers include classical enhancers and facilitators to fully activate gene expression. Cell 186, 5826–5839.e5818 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Mogilenko, D. A., Shchukina, I. & Artyomov, M. N. Immune ageing at single-cell resolution. Nat. Rev. Immunol. 22, 484–498 (2022).

    Article  CAS  PubMed  Google Scholar 

  157. Goodell, M. A. & Rando, T. A. Stem cells and healthy aging. Science 350, 1199–1204 (2015).

    Article  CAS  PubMed  Google Scholar 

  158. Sun, D. et al. Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell 14, 673–688 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Tang, B. et al. Aging-disturbed FUS phase transition impairs hematopoietic stem cells by altering chromatin structure. Blood 143, 124–138 (2024).

    Article  CAS  PubMed  Google Scholar 

  160. Lv, K. et al. HectD1 controls hematopoietic stem cell regeneration by coordinating ribosome assembly and protein synthesis. Cell Stem Cell 28, 1275–1290.e1279 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Maneix, L. et al. Cyclophilin A supports translation of intrinsically disordered proteins and affects haematopoietic stem cell ageing. Nat. Cell Biol. 26, 593–603 (2024). This study links impaired chaperone support for translation of key condensate regulators to haematopoietic stem cell ageing.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Flach, J. et al. Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature 512, 198–202 (2014). This work connects nucleolar stress signalling to impaired ribosome assembly and the age-associated decline of haematopoietic stem cell function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Morganti, C. et al. NPM1 ablation induces HSC aging and inflammation to develop myelodysplastic syndrome exacerbated by p53 loss. EMBO Rep. 23, e54262 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Boisvert, F. M., van Koningsbruggen, S., Navascues, J. & Lamond, A. I. The multifunctional nucleolus. Nat. Rev. Mol. Cell Biol. 8, 574–585 (2007).

    Article  CAS  PubMed  Google Scholar 

  165. Salim, D. et al. DNA replication stress restricts ribosomal DNA copy number. PLoS Genet. 13, e1007006 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Mitchell, C. in Genetics and Development. PhD thesis, Columbia Univ. Irving Medical Center (2024).

  167. Perry, R. P. The cellular sites of synthesis of ribosomal and 4s RNA. Proc. Natl Acad. Sci. USA 48, 2179–2186 (1962).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Brunetti, L. et al. Mutant NPM1 maintains the leukemic state through HOX expression. Cancer Cell 34, 499–512.e499 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Oka, M. et al. Chromatin-bound CRM1 recruits SET-Nup214 and NPM1c onto HOX clusters causing aberrant HOX expression in leukemia cells. Elife 8, e46667 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Wang, X. Q. D. et al. Mutant NPM1 hijacks transcriptional hubs to maintain pathogenic gene programs in acute myeloid leukemia. Cancer Discov. 13, 724–745 (2023). This work indicates that a mutant form of the nucleolar protein NPM1, which is commonly expressed in acute myeloid leukaemia, can bind specific chromatin regions and form aberrant transcriptional condensates that sustain transcription of leukaemic genes.

    Article  PubMed  Google Scholar 

  171. Uckelmann, H. J. et al. Mutant NPM1 directly regulates oncogenic transcription in acute myeloid leukemia. Cancer Discov. 13, 746–765 (2023). This study also supports a model in which mutant NPM1 binds specific chromatin targets and forms transcriptional condensates that maintain leukaemic transcription.

    Article  PubMed  PubMed Central  Google Scholar 

  172. Liu, Y. et al. Condensate-promoting ENL mutation drives tumorigenesis in vivo through dynamic regulation of histone modifications and gene expression. Cancer Discov. 14, 1522–1546 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Song, L. et al. Hotspot mutations in the structured ENL YEATS ___domain link aberrant transcriptional condensates and cancer. Mol. Cell 82, 4080–4098.e4012 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Guo, C. et al. ENL initiates multivalent phase separation of the super elongation complex (SEC) in controlling rapid transcriptional activation. Sci. Adv. 6, eaay4858 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Sanalkumar, R. et al. Highly connected 3D chromatin networks established by an oncogenic fusion protein shape tumor cell identity. Sci. Adv. 9, eabo3789 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Quiroga, I. Y., Ahn, J. H., Wang, G. G. & Phanstiel, D. Oncogenic fusion proteins and their role in three-dimensional chromatin structure, phase separation, and cancer. Curr. Opin. Genet. Dev. 74, 101901 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Nussenzweig, A. & Nussenzweig, M. C. Origin of chromosomal translocations in lymphoid cancer. Cell 141, 27–38 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Riedel, S. S. et al. Intrinsically disordered Meningioma-1 stabilizes the BAF complex to cause AML. Mol. Cell 81, 2332–2348.e2339 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. 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 

  180. Chandra, B. et al. Phase separation mediates NUP98 fusion oncoprotein leukemic transformation. Cancer Discov. 12, 1152–1169 (2022).

    Article  CAS  PubMed  Google Scholar 

  181. Oka, M. et al. Phase-separated nuclear bodies of nucleoporin fusions promote condensation of MLL1/CRM1 and rearrangement of 3D genome structure. Cell Rep. 42, 112884 (2023).

    Article  CAS  PubMed  Google Scholar 

  182. Michmerhuizen, N. L., Klco, J. M. & Mullighan, C. G. Mechanistic insights and potential therapeutic approaches for NUP98-rearranged hematologic malignancies. Blood 136, 2275–2289 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  183. Voisset, E. et al. Pml nuclear body disruption cooperates in APL pathogenesis and impairs DNA damage repair pathways in mice. Blood 131, 636–648 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Daniel, M. T. et al. PML protein expression in hematopoietic and acute promyelocytic leukemia cells. Blood 82, 1858–1867 (1993).

    Article  CAS  PubMed  Google Scholar 

  185. Dyck, J. A. et al. A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein. Cell 76, 333–343 (1994).

    Article  CAS  PubMed  Google Scholar 

  186. Bercier, P. et al. Structural basis of PML–RARA oncoprotein targeting by arsenic unravels a cysteine rheostat controlling PML body assembly and function. Cancer Discov. 13, 2548–2565 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Zhang, Y. et al. Phase separation of PML/RARα and BRD4 coassembled microspeckles governs transcriptional dysregulation in acute promyelocytic leukemia. Proc. Natl Acad. Sci. USA 121, e2406519121 (2024). This study uncovers an unexpected function for PML condensates in acute promyelocytic leukaemia, showing that they sequester the transcription cofactor BRD4, redistributing it to oncogenic super-enhancers and broad promoters, thereby promoting leukaemic gene transcription.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Pi, W. C. et al. E2A–PBX1 functions as a coactivator for RUNX1 in acute lymphoblastic leukemia. Blood 136, 11–23 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  189. Lee, Y. L. et al. Mediator subunit MED1 is required for E2A–PBX1-mediated oncogenic transcription and leukemic cell growth. Proc. Natl Acad. Sci. USA 118, e1922864118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Gozdecka, M. et al. UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs. Nat. Genet. 50, 883–894 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Shi, B. et al. UTX condensation underlies its tumour-suppressive activity. Nature 597, 726–731 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Dominguez, P. M. et al. TET2 deficiency causes germinal center hyperplasia, impairs plasma cell differentiation, and promotes B-cell lymphomagenesis. Cancer Discov. 8, 1632–1653 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Delhommeau, F. et al. Mutation in TET2 in myeloid cancers. N. Engl. J. Med. 360, 2289–2301 (2009).

    Article  PubMed  Google Scholar 

  194. Couronne, L., Bastard, C. & Bernard, O. A. TET2 and DNMT3A mutations in human T-cell lymphoma. N. Engl. J. Med. 366, 95–96 (2012).

    Article  CAS  PubMed  Google Scholar 

  195. Guo, L. et al. Perturbing TET2 condensation promotes aberrant genome-wide DNA methylation and curtails leukaemia cell growth. Nat. Cell Biol. 26, 2154–2167 (2024).

    Article  CAS  PubMed  Google Scholar 

  196. Wu, X. & Zhang, Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat. Rev. Genet. 18, 517–534 (2017).

    Article  CAS  PubMed  Google Scholar 

  197. Fonteneau, G. et al. Stress granules determine the development of obesity-associated pancreatic cancer. Cancer Discov. 12, 1984–2005 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Biancon, G. et al. Precision analysis of mutant U2AF1 activity reveals deployment of stress granules in myeloid malignancies. Mol. Cell 82, 1107–1122.e1107 (2022). This work reveals stress granule components as targets of aberrant splicing in malignant myeloid cells, which leads to increased stress granule formation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Truitt, M. L. & Ruggero, D. New frontiers in translational control of the cancer genome. Nat. Rev. Cancer 16, 288–304 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Paris, J. et al. Targeting the RNA m6A reader YTHDF2 selectively compromises cancer stem cells in acute myeloid leukemia. Cell Stem Cell 25, 137–148.e136 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Barbieri, I. et al. Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control. Nature 552, 126–131 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Vu, L. P. et al. The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat. Med. 23, 1369–1376 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Li, Z. et al. FTO plays an oncogenic role in acute myeloid leukemia as a N6-methyladenosine RNA demethylase. Cancer Cell 31, 127–141 (2017).

    Article  PubMed  Google Scholar 

  204. Shen, C. et al. RNA demethylase ALKBH5 selectively promotes tumorigenesis and cancer stem cell self-renewal in acute myeloid leukemia. Cell Stem Cell 27, 64–80 e69 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Meyer, K. D. & Jaffrey, S. R. Rethinking m6A readers, writers, and erasers. Annu. Rev. Cell Dev. Biol. 33, 319–342 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Cheng, Y. et al. N6-methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation. Cancer Cell 39, 958–972.e958 (2021). This study connects aberrant nuclear condensate formation to the misregulation of m6A-modified RNAs in the context of myeloid leukaemia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Zhu, G. et al. Phase separation of disease-associated SHP2 mutants underlies MAPK hyperactivation. Cell 183, 490–502.e418 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Pandey, R., Saxena, M. & Kapur, R. Role of SHP2 in hematopoiesis and leukemogenesis. Curr. Opin. Hematol. 24, 307–313 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Bracha, D., Walls, M. T. & Brangwynne, C. P. Probing and engineering liquid-phase organelles. Nat. Biotechnol. 37, 1435–1445 (2019).

    Article  CAS  PubMed  Google Scholar 

  210. Dai, Y., You, L. & Chilkoti, A. Engineering synthetic biomolecular condensates. Nat. Rev. Bioeng. 1, 466–480 (2023).

  211. Femino, A. M., Fay, F. S., Fogarty, K. & Singer, R. H. Visualization of single RNA transcripts in situ. Science 280, 585–590 (1998).

    Article  CAS  PubMed  Google Scholar 

  212. Xia, C., Colognori, D., Jiang, X., Xu, K. & Doudna, J. A. Single-molecule live-cell RNA imaging with CRISPR-Csm. Preprint at bioRxiv https://doi.org/10.1101/2024.07.14.603457 (2024).

  213. Qin, W., Cho, K. F., Cavanagh, P. E. & Ting, A. Y. Deciphering molecular interactions by proximity labeling. Nat. Methods 18, 133–143 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Ren, J., Luo, S., Shi, H. & Wang, X. Spatial omics advances for in situ RNA biology. Mol. Cell 84, 3737–3757 (2024).

    Article  CAS  PubMed  Google Scholar 

  215. Wang, X. et al. N6-methyladenosine modification of MALAT1 promotes metastasis via reshaping nuclear speckles. Dev. Cell 56, 702–715.e708 (2021).

    Article  CAS  PubMed  Google Scholar 

  216. Markmiller, S. et al. Context-dependent and disease-specific diversity in protein interactions within stress granules. Cell 172, 590–604.e513 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Lam, S. S. et al. Directed evolution of APEX2 for electron microscopy and proximity labeling. Nat. Methods 12, 51–54 (2015).

    Article  CAS  PubMed  Google Scholar 

  218. Lobingier, B. T. et al. An approach to spatiotemporally resolve protein interaction networks in living cells. Cell 169, 350–360.e312 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Brangwynne, C. P. et al. Germline P granules are liquid droplets that localize by controlled dissolution/condensation. Science 324, 1729–1732 (2009).

    Article  CAS  PubMed  Google Scholar 

  220. Feric, M. et al. Coexisting liquid phases underlie nucleolar subcompartments. Cell 165, 1686–1697 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Frottin, F. et al. The nucleolus functions as a phase-separated protein quality control compartment. Science 365, 342–347 (2019).

    Article  CAS  PubMed  Google Scholar 

  222. Brangwynne, C. P., Mitchison, T. J. & Hyman, A. A. Active liquid-like behavior of nucleoli determines their size and shape in Xenopus laevis oocytes. Proc. Natl Acad. Sci. USA 108, 4334–4339 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Patel, A. et al. A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162, 1066–1077 (2015).

    Article  CAS  PubMed  Google Scholar 

  224. Shin, Y. et al. Liquid nuclear condensates mechanically sense and restructure the genome. Cell 175, 1481–1491.e1413 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Alberti, S., Gladfelter, A. & Mittag, T. Considerations and challenges in studying liquid-liquid phase separation and biomolecular condensates. Cell 176, 419–434 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. 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 

  227. Lyon, A. S., Peeples, W. B. & Rosen, M. K. A framework for understanding the functions of biomolecular condensates across scales. Nat. Rev. Mol. Cell Biol. 22, 215–235 (2021).

    Article  CAS  PubMed  Google Scholar 

  228. Yang, J. et al. MYC phase separation selectively modulates the transcriptome. Nat. Struct. Mol. Biol. 31, 1567–1579 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank all members of the Di Stefano lab for stimulating discussions. We also thank R. Stadhouders, J. Lee, G. K. Datar and J. A. Riback for their insightful comments on the manuscript. B.D.S. is a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research. B.D.S. is supported by the CPRIT Recruitment of First-Time, Tenure-Track Faculty Member Award RR200079, the American Society of Hematology (ASH) Scholar Award, the Andrew McDonough B+ Foundation (AMBF), the Worldwide Cancer Research (WCR) Foundation, the Milky Way Research Foundation Investigator Award and the NIH National Institute of General Medical Sciences Maximizing Investigators’ Research Award 1R35GM147126-01. S.K. is supported by NIH National Cancer Institute 1F32CA288043-01. C.M.S. is supported by NIH grant T32DK060445.

Author information

Authors and Affiliations

Authors

Contributions

All authors researched data for the article, contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission. C.M.S. prepared the original artwork and contributed to the writing. S.K. and B.D.S. wrote the article.

Corresponding author

Correspondence to Bruno Di Stefano.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Immunology thanks Thomas Graf, Gregoire Stik and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kodali, S., Sands, C.M., Guo, L. et al. Biomolecular condensates in immune cell fate. Nat Rev Immunol 25, 445–459 (2025). https://doi.org/10.1038/s41577-025-01130-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41577-025-01130-z

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing