DNA architectural protein CTCF facilitates subset-specific chromatin interactions to limit the formation of memory CD8+ T cells

Sara Quon; Bingfei Yu; Brendan E Russ; Kirill Tsyganov; Hongtuyet Nguyen; Clara Toma; Maximilian Heeg; James D Hocker; J Justin Milner; Shane Crotty; Matthew E Pipkin; Stephen J Turner; Ananda W Goldrath

doi:10.1016/j.immuni.2023.03.017

DNA architectural protein CTCF facilitates subset-specific chromatin interactions to limit the formation of memory CD8⁺ T cells

Immunity. 2023 May 9;56(5):959-978.e10. doi: 10.1016/j.immuni.2023.03.017. Epub 2023 Apr 10.

Authors

Affiliations

¹ School of Biological Sciences, Department of Molecular Biology, University of California, San Diego, La Jolla, CA 92093, USA.
² Department of Microbiology, Immunity Theme, Biomedical Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
³ Department of Microbiology, Immunity Theme, Biomedical Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Bioinformatics Platform, Biomedical Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
⁴ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA 92037, USA.
⁵ Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL 33458, USA.
⁶ Department of Microbiology, Immunity Theme, Biomedical Discovery Institute, Monash University, Clayton, VIC 3800, Australia. Electronic address: stephen.j.turner@monash.edu.
⁷ School of Biological Sciences, Department of Molecular Biology, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: agoldrath@ucsd.edu.

PMID: 37040762
PMCID: PMC10265493 (available on 2024-05-09)
DOI: 10.1016/j.immuni.2023.03.017

Abstract

Although the importance of genome organization for transcriptional regulation of cell-fate decisions and function is clear, the changes in chromatin architecture and how these impact effector and memory CD8⁺ T cell differentiation remain unknown. Using Hi-C, we studied how genome configuration is integrated with CD8⁺ T cell differentiation during infection and investigated the role of CTCF, a key chromatin remodeler, in modulating CD8⁺ T cell fates through CTCF knockdown approaches and perturbation of specific CTCF-binding sites. We observed subset-specific changes in chromatin organization and CTCF binding and revealed that weak-affinity CTCF binding promotes terminal differentiation of CD8⁺ T cells through the regulation of transcriptional programs. Further, patients with de novo CTCF mutations had reduced expression of the terminal-effector genes in peripheral blood lymphocytes. Therefore, in addition to establishing genome architecture, CTCF regulates effector CD8⁺ T cell heterogeneity through altering interactions that regulate the transcription factor landscape and transcriptome.

Keywords: CD8(+) T cell; CTCF; Hi-C; enhancer; epigenetics; genome organization; promoter.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
CCCTC-Binding Factor / metabolism
CD8-Positive T-Lymphocytes / metabolism
Chromatin*
DNA / metabolism
Humans
Protein Binding
Repressor Proteins* / genetics
Repressor Proteins* / metabolism

Substances

CCCTC-Binding Factor
Chromatin
DNA
Repressor Proteins
CTCF protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding