Cbfβ regulates DNA looping at the Il4-Il13 loci to control their differential expression in Th2 cells
Th2 cells play a central role in orchestrating type 2 immune responses by producing type 2 cytokines including IL-4 and IL-13. The master transcription factor GATA3 is essential but not sufficient for type 2 cytokine production. To better define other transcription factors that regulate type 2 cytokine expression, we performed a CRISPR-Cas9 screen after preparing a retroviral library expressing sgRNAs targeting 2,394 mouse transcription factors and cofactors. The screen revealed core-binding factor beta (Cbfβ) as a specific inducer of IL-13 that simultaneously inhibited IL-4 expression. The effect of Cbfβ on IL-13 production was confirmed both in vitro and in vivo and was independent of GATA3 induction. Mechanistically, Cbfβ induced chromatin accessibility at the HS-2 site within the Il13 promoter where the Cbfβ/Runx complex bound. Hi-TrAC analysis indicated that DNA looping between HS-2 and other enhancers was reduced upon Cbfβ deletion. Overall, our results indicate that Cbfβ directly regulates IL-13 expression by binding the Il13 promoter via the Cbfβ/Runx complex and promoting enhancer-promoter interactions that facilitate Il13 transcription.
Authors
- Dominic P. Golec (ORCID: https://orcid.org/0000-0002-2741-3302)
- Helen C. Su (ORCID: https://orcid.org/0000-0002-5582-9110)
- Chih-Yuan Chiang (ORCID: https://orcid.org/0009-0009-3215-8287)
- Difeng Fang (ORCID: https://orcid.org/0000-0003-2105-6743)
- Danping Wei (ORCID: https://orcid.org/0009-0009-8828-8523)
- Huie Jing (ORCID: https://orcid.org/0000-0001-6283-3452)
- Ken Chih-Chien Cheng (ORCID: https://orcid.org/0000-0003-0437-5697)
- Guangzhe Ge (ORCID: https://orcid.org/0009-0007-0226-0374)
- Keji Zhao (ORCID: https://orcid.org/0000-0001-5559-6233)
- Pamela L. Schwartzberg (ORCID: https://orcid.org/0000-0001-6318-9187)
- Yaqiang Cao (ORCID: https://orcid.org/0000-0002-4665-1517)
- Jinfang Zhu (ORCID: https://orcid.org/0000-0002-0117-4745)
- Hirofumi Shibata (ORCID: https://orcid.org/0000-0002-8798-2611)
- Zoey J Kline (ORCID: https://orcid.org/0009-0004-2604-9141)
Institutions
- National Institutes of Health (US)
- National Heart, Lung, and Blood Institute (US)
- National Institute of Allergy and Infectious Diseases (US)
- National Center for Advancing Translational Sciences (US)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2026-10-28
- DOI
- https://doi.org/10.1084/jem.20260418
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Health and Human Services
- National Institutes of Health
- Intramural Research Program