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; Hiroyuki Nagashima; Nilisha Fernando; Victor Bass; Jaanam Gopalakrishnan; Sadie Signorella; Will Montgomery; Ai Ing Lim; Oliver Harrison; Lauren Reich; Chen Yao; Hong Wei Sun; Stephen R. Brooks; Kan Jiang; Vijayaraj Nagarajan; Yongbing Zhao; Seolkyoung Jung; Rachael Phillips; Yohei Mikami; Caleb A. Lareau; Yuka Kanno; Dragana Jankovic; Martin J. Aryee; Aleksandra Pękowska; Yasmine Belkaid; John O'Shea; Han Yu Shih

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, Hiroyuki Nagashima, Nilisha Fernando, Victor Bass, Jaanam Gopalakrishnan, Sadie Signorella, Will Montgomery, Ai Ing Lim, Oliver Harrison, Lauren Reich, Chen Yao, Hong Wei Sun, Stephen R. Brooks, Kan Jiang, Vijayaraj Nagarajan, Yongbing Zhao, Seolkyoung Jung, Rachael Phillips, Yohei Mikami, Caleb A. LareauYuka Kanno, Dragana Jankovic, Martin J. Aryee, Aleksandra Pękowska, Yasmine Belkaid, John O'Shea, Han Yu Shih

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	1005-1018.e7
Journal	Immunity
Volume	57
Issue number	5
DOIs	https://doi.org/10.1016/j.immuni.2024.04.007
State	Published - May 14 2024
Externally published	Yes

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Immunology
Infectious Diseases

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

Access to Document

10.1016/j.immuni.2024.04.007

Cite this

Liu, C., Nagashima, H., Fernando, N., Bass, V., Gopalakrishnan, J., Signorella, S., Montgomery, W., Lim, A. I., Harrison, O., Reich, L., Yao, C., Sun, H. W., Brooks, S. R., Jiang, K., Nagarajan, V., Zhao, Y., Jung, S., Phillips, R., Mikami, Y., ... Shih, H. Y. (2024). 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. Immunity, 57(5), 1005-1018.e7. https://doi.org/10.1016/j.immuni.2024.04.007

@article{62e86e07b5c74a3093e3d90353658d97,

title = "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",

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",

author = "Chunhong Liu and Hiroyuki Nagashima and Nilisha Fernando and Victor Bass and Jaanam Gopalakrishnan and Sadie Signorella and Will Montgomery and Lim, {Ai Ing} and Oliver Harrison and Lauren Reich and Chen Yao and Sun, {Hong Wei} and Brooks, {Stephen R.} and Kan Jiang and Vijayaraj Nagarajan and Yongbing Zhao and Seolkyoung Jung and Rachael Phillips and Yohei Mikami and Lareau, {Caleb A.} and Yuka Kanno and Dragana Jankovic and Aryee, {Martin J.} and Aleksandra P{\c e}kowska and Yasmine Belkaid and John O'Shea and Shih, {Han Yu}",

note = "Publisher Copyright: {\textcopyright} 2024",

year = "2024",

month = may,

day = "14",

doi = "10.1016/j.immuni.2024.04.007",

language = "English (US)",

volume = "57",

pages = "1005--1018.e7",

journal = "Immunity",

issn = "1074-7613",

publisher = "Cell Press",

number = "5",

}

Liu, C, Nagashima, H, Fernando, N, Bass, V, Gopalakrishnan, J, Signorella, S, Montgomery, W, Lim, AI, Harrison, O, Reich, L, Yao, C, Sun, HW, Brooks, SR, Jiang, K, Nagarajan, V, Zhao, Y, Jung, S, Phillips, R, Mikami, Y, Lareau, CA, Kanno, Y, Jankovic, D, Aryee, MJ, Pękowska, A, Belkaid, Y, O'Shea, J & Shih, HY 2024, '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', Immunity, vol. 57, no. 5, pp. 1005-1018.e7. https://doi.org/10.1016/j.immuni.2024.04.007

TY - JOUR

T1 - 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

AU - Liu, Chunhong

AU - Nagashima, Hiroyuki

AU - Fernando, Nilisha

AU - Bass, Victor

AU - Gopalakrishnan, Jaanam

AU - Signorella, Sadie

AU - Montgomery, Will

AU - Lim, Ai Ing

AU - Harrison, Oliver

AU - Reich, Lauren

AU - Yao, Chen

AU - Sun, Hong Wei

AU - Brooks, Stephen R.

AU - Jiang, Kan

AU - Nagarajan, Vijayaraj

AU - Zhao, Yongbing

AU - Jung, Seolkyoung

AU - Phillips, Rachael

AU - Mikami, Yohei

AU - Lareau, Caleb A.

AU - Kanno, Yuka

AU - Jankovic, Dragana

AU - Aryee, Martin J.

AU - Pękowska, Aleksandra

AU - Belkaid, Yasmine

AU - O'Shea, John

AU - Shih, Han Yu

PY - 2024/5/14

Y1 - 2024/5/14

N2 - 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.

AB - 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.

KW - CBSs

KW - CTCF

KW - Hi-C

KW - Th1

KW - Th17

KW - Toxoplasma gondii

KW - interferon-gamma

KW - interleukin-22

KW - lymphocytic choriomeningitis virus

KW - natural killer cells

KW - super-enhancers

KW - three-dimensional

KW - topologically associating domains

UR - http://www.scopus.com/inward/record.url?scp=85192251718&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85192251718&partnerID=8YFLogxK

U2 - 10.1016/j.immuni.2024.04.007

DO - 10.1016/j.immuni.2024.04.007

M3 - Article

C2 - 38697116

AN - SCOPUS:85192251718

SN - 1074-7613

VL - 57

SP - 1005-1018.e7

JO - Immunity

JF - Immunity

IS - 5

ER -

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

Abstract

All Science Journal Classification (ASJC) codes

Keywords

Access to Document

Other files and links

Fingerprint

Cite this