A CTCF-binding site in the Mdm1-Il22-Ifng locus shapes cytokine expression profiles and plays a critical role in early Th1 cell fate specification

doi:10.1016/j.immuni.2024.04.007

. 2024 May 14;57(5):1005-1018.e7.

doi: 10.1016/j.immuni.2024.04.007. Epub 2024 May 1.

A CTCF-binding site in the Mdm1-Il22-Ifng locus shapes cytokine expression profiles and plays a critical role in early Th1 cell fate specification

Chunhong Liu¹, Hiroyuki Nagashima², Nilisha Fernando¹, Victor Bass¹, Jaanam Gopalakrishnan¹, Sadie Signorella³, Will Montgomery¹, Ai Ing Lim⁴, Oliver Harrison⁴, Lauren Reich¹, Chen Yao², Hong-Wei Sun⁵, Stephen R Brooks⁵, Kan Jiang⁵, Vijayaraj Nagarajan¹, Yongbing Zhao², Seolkyoung Jung², Rachael Phillips², Yohei Mikami², Caleb A Lareau⁶, Yuka Kanno², Dragana Jankovic⁷, Martin J Aryee⁶, Aleksandra Pękowska⁸, Yasmine Belkaid⁴, John O'Shea², Han-Yu Shih⁹

Affiliations

¹ Neuro-Immune Regulome Unit, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
² Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
³ Neuro-Immune Regulome Unit, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA; Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
⁴ Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁷ Immunoparasitology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
⁸ Dioscuri Center of Chromatin Biology and Epigenomics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
⁹ Neuro-Immune Regulome Unit, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: han-yu.shih@nih.gov.

PMID: 38697116
PMCID: PMC11108081 (available on 2025-05-14)
DOI: 10.1016/j.immuni.2024.04.007

A CTCF-binding site in the Mdm1-Il22-Ifng locus shapes cytokine expression profiles and plays a critical role in early Th1 cell fate specification

Chunhong Liu et al. Immunity. 2024.

. 2024 May 14;57(5):1005-1018.e7.

doi: 10.1016/j.immuni.2024.04.007. Epub 2024 May 1.

Authors

Affiliations

¹ Neuro-Immune Regulome Unit, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
² Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
³ Neuro-Immune Regulome Unit, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA; Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
⁴ Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁷ Immunoparasitology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
⁸ Dioscuri Center of Chromatin Biology and Epigenomics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
⁹ Neuro-Immune Regulome Unit, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: han-yu.shih@nih.gov.

PMID: 38697116
PMCID: PMC11108081 (available on 2025-05-14)
DOI: 10.1016/j.immuni.2024.04.007

Abstract

Cytokine expression during T cell differentiation is a highly regulated process that involves long-range promoter-enhancer and CTCF-CTCF contacts at cytokine loci. Here, we investigated the impact of dynamic chromatin loop formation within the topologically associating domain (TAD) in regulating the expression of interferon gamma (IFN-γ) and interleukin-22 (IL-22); these cytokine loci are closely located in the genome and are associated with complex enhancer landscapes, which are selectively active in type 1 and type 3 lymphocytes. In situ Hi-C analyses revealed inducible TADs that insulated Ifng and Il22 enhancers during Th1 cell differentiation. Targeted deletion of a 17 bp boundary motif of these TADs imbalanced Th1- and Th17-associated immunity, both in vitro and in vivo, upon Toxoplasma gondii infection. In contrast, this boundary element was dispensable for cytokine regulation in natural killer cells. Our findings suggest that precise cytokine regulation relies on lineage- and developmental stage-specific interactions of 3D chromatin architectures and enhancer landscapes.

Keywords: CBSs; CTCF; Hi-C; Th1; Th17; Toxoplasma gondii; interferon-gamma; interleukin-22; lymphocytic choriomeningitis virus; natural killer cells; super-enhancers; three-dimensional; topologically associating domains.

Published by Elsevier Inc.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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Adams NM, Galitsyna A, Tiniakou I, Esteva E, Lau CM, Reyes J, Abdennur N, Shkolikov A, Yap GS, Khodadadi-Jamayran A, Mirny LA, Reizis B. Adams NM, et al. bioRxiv [Preprint]. 2024 Oct 30:2024.09.18.613709. doi: 10.1101/2024.09.18.613709. bioRxiv. 2024. PMID: 39345451 Free PMC article. Preprint.

References

1. Rowley MJ, and Corces VG (2018). Organizational principles of 3D genome architecture. Nat Rev Genet 19, 789–800. 10.1038/s41576-018-0060-8. - DOI - PMC - PubMed
1. Dixon JR, Gorkin DU, and Ren B (2016). Chromatin Domains: The Unit of Chromosome Organization. Mol Cell 62, 668–680. 10.1016/j.molcel.2016.05.018. - DOI - PMC - PubMed
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[1] Rowley MJ, and Corces VG (2018). Organizational principles of 3D genome architecture. Nat Rev Genet 19, 789–800. 10.1038/s41576-018-0060-8. - DOI - PMC - PubMed

[2] Rowley MJ, and Corces VG (2018). Organizational principles of 3D genome architecture. Nat Rev Genet 19, 789–800. 10.1038/s41576-018-0060-8. - DOI - PMC - PubMed

[3] Dixon JR, Gorkin DU, and Ren B (2016). Chromatin Domains: The Unit of Chromosome Organization. Mol Cell 62, 668–680. 10.1016/j.molcel.2016.05.018. - DOI - PMC - PubMed

[4] Dixon JR, Gorkin DU, and Ren B (2016). Chromatin Domains: The Unit of Chromosome Organization. Mol Cell 62, 668–680. 10.1016/j.molcel.2016.05.018. - DOI - PMC - PubMed

[5] Davidson IF, and Peters JM (2021). Genome folding through loop extrusion by SMC complexes. Nat Rev Mol Cell Biol 22, 445–464. 10.1038/s41580-021-00349-7. - DOI - PubMed

[6] Davidson IF, and Peters JM (2021). Genome folding through loop extrusion by SMC complexes. Nat Rev Mol Cell Biol 22, 445–464. 10.1038/s41580-021-00349-7. - DOI - PubMed

[7] Xiang JF, and Corces VG (2021). Regulation of 3D chromatin organization by CTCF. Curr Opin Genet Dev 67, 33–40. 10.1016/j.gde.2020.10.005. - DOI - PMC - PubMed

[8] Xiang JF, and Corces VG (2021). Regulation of 3D chromatin organization by CTCF. Curr Opin Genet Dev 67, 33–40. 10.1016/j.gde.2020.10.005. - DOI - PMC - PubMed

[9] Nichols MH, and Corces VG (2015). A CTCF Code for 3D Genome Architecture. Cell 162, 703–705. 10.1016/j.cell.2015.07.053. - DOI - PMC - PubMed

[10] Nichols MH, and Corces VG (2015). A CTCF Code for 3D Genome Architecture. Cell 162, 703–705. 10.1016/j.cell.2015.07.053. - DOI - PMC - PubMed

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A CTCF-binding site in the Mdm1-Il22-Ifng locus shapes cytokine expression profiles and plays a critical role in early Th1 cell fate specification

Affiliations

A CTCF-binding site in the Mdm1-Il22-Ifng locus shapes cytokine expression profiles and plays a critical role in early Th1 cell fate specification

Authors

Affiliations

Abstract

Conflict of interest statement

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Abstract

Conflict of interest statement

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