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Epigenetics control lineage decisions during hematopoiesis of innate lymphocytes

Cellular & Molecular Immunology (2026)Cite this article

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Innate lymphoid cells (ILCs) are master regulators of mucosal immunity [1], but the pathways shaping their hematopoiesis and dictating lineage-fate decisions remain poorly understood. In a recent study reported in Nature Immunology [2], Liu et al. simultaneously profiled the DNA methylation, chromatin accessibility, and transcriptome characteristics of ILC precursors (ILCPs) and mature ILC subsets via single-cell multiomics techniques and a genomic methylation reporter system. The results of this study revealed that ILCPs segregate into two distinct clusters on the basis of unique DNA methylation features, with further functional studies revealing that these ILCPs employ key epigenomic machinery to dictate lineage segregation of ILC subsets during the precursor stage of development.

DNA methylation is a critical and well-characterized epigenetic modification that is of paramount importance for mammalian embryonic development and influences cell fate and functional differentiation in all stages of somatic cell development [3]. ILCs are a family of innate lymphocytes, categorized as ILC1s, ILC2s, and ILC3s, which do not have somatically recombined receptors for activation. ILCs are predominantly tissue-resident lymphocytes throughout the body and are enriched at mucosal barriers, where they play key roles in maintaining tissue homeostasis, immunity and inflammation [1]. Conventional ILCs develop from common lymphoid progenitors (CLPs) that differentiate into common helper ILC progenitors (CHILPs) and then into ILCPs in the bone marrow or fetal liver, which can give rise to mature ILC1, ILC2, and ILC3 populations [4, 5]. Recent studies have demonstrated that specialized transcriptional diversity, epigenomic states, and metabolic activity imprint ILC progenitors or subsets. This includes a key role for the microbiota in shaping the transcriptional landscape and epigenomic profile of ILC populations in mice [6]. Additional data indicate that during development, prior to the expression of lineage-determining transcription factors for terminal differentiation, ILC functionality is predetermined by epigenomic regulatory elements such as DNA methylation, histone modifications, and chromatin accessibility [7]. This is not restricted to studies in mice, as human ILC regulome analyses of gene expression programs and gene regulatory schematics revealed important aspects of their developmental or functional relationships [8]. Although single-cell genomics enables unbiased characterization of cell types and is an effective tool for systematically resolving ILC heterogeneity, the limitations of current technologies and the potential plasticity between ILC subsets pose significant challenges in characterizing the early fate-determining factors and dynamics of epigenetic modifications that control the differentiation of ILCPs into distinct ILC subsets.

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Fig. 1: Schematic depicting how epigenomics impacts the fate decisions of innate lymphocyte progenitors.

References

  1. Vivier E, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, et al. Innate Lymphoid Cells: 10 Years On. Cell. 2018;174:1054–66. https://doi.org/10.1016/j.cell.2018.07.017.

    Article  CAS  PubMed  Google Scholar 

  2. Liu Z, Shao F, Zhang Q, Zhao M, Gao S, Zhang X, et al. Epigenetic imprinting in innate lymphoid cell precursors directs the lineage segregation of innate lymphoid cells. Nat Immunol. 2025;26:1686–98. https://doi.org/10.1038/s41590-025-02261-0.

    Article  CAS  PubMed  Google Scholar 

  3. Smith ZD, Hetzel S, Meissner A. DNA methylation in mammalian development and disease. Nat Rev Genet. 2025;26:7–30. https://doi.org/10.1038/s41576-024-00760-8.

    Article  CAS  PubMed  Google Scholar 

  4. Constantinides MG, McDonald BD, Verhoef PA, Bendelac A. A committed precursor to innate lymphoid cells. Nature. 2014;508:397–401. https://doi.org/10.1038/nature13047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Klose CSN, Flach M, Möhle L, Rogell L, Hoyler T, Ebert K, et al. Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell. 2014;157:340–56. https://doi.org/10.1016/j.cell.2014.03.030.

    Article  CAS  PubMed  Google Scholar 

  6. Gury-BenAri M, Thaiss CA, Serafini N, Winter DR, Giladi A, Lara-Astiaso D, et al. The spectrum and regulatory landscape of intestinal innate lymphoid cells are shaped by the microbiome. Cell. 2016;166:1231–46.e1213. https://doi.org/10.1016/j.cell.2016.07.043.

    Article  CAS  PubMed  Google Scholar 

  7. Shih HY, Sciumè G, Mikami Y, Guo L, Sun HW, Brooks SR, et al. Developmental acquisition of regulomes underlies innate lymphoid cell functionality. Cell. 2016;165:1120–33. https://doi.org/10.1016/j.cell.2016.04.029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Koues OI, Collins PL, Cella M, Robinette ML, Porter SI, Pyfrom SC, et al. Distinct gene regulatory pathways for human innate versus adaptive lymphoid cells. Cell. 2016;165:1134–46. https://doi.org/10.1016/j.cell.2016.04.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhang X, Gao X, Liu Z, Shao F, Yu D, Zhao M, et al. Microbiota regulates the TET1-mediated DNA hydroxymethylation program in innate lymphoid cell differentiation. Nat Commun. 2024;15:4792. https://doi.org/10.1038/s41467-024-48794-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Peng V, Xing X, Bando JK, Trsan T, Di Luccia B, Collins PL, et al. Whole-genome profiling of DNA methylation and hydroxymethylation identifies distinct regulatory programs among innate lymphocytes. Nat Immunol. 2022;23:619–31. https://doi.org/10.1038/s41590-022-01164-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lim AI, Li Y, Lopez-Lastra S, Stadhouders R, Paul F, Casrouge A, et al. Systemic human ILC precursors provide a substrate for tissue ILC differentiation. Cell. 2017;168:1086–100.e1010. https://doi.org/10.1016/j.cell.2017.02.021.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology & Hepatology, Weill Cornell Medicine, Cornell University, New York, NY, USA

    Lan Kang & Gregory F. Sonnenberg

  2. Department of Microbiology & Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA

    Lan Kang & Gregory F. Sonnenberg

  3. Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA

    Lan Kang & Gregory F. Sonnenberg

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Correspondence to Gregory F. Sonnenberg.

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Kang, L., Sonnenberg, G.F. Epigenetics control lineage decisions during hematopoiesis of innate lymphocytes. Cell Mol Immunol (2026). https://doi.org/10.1038/s41423-025-01384-6

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