Quantitative control of Ets1 dosage by a multi-enhancer hub promotes Th1 cell differentiation and protects from allergic inflammation

• Published in: Immunity (Cambridge, Mass.) Mass.), 2023-07, Vol.56 (7), p.1451-1467.e12
• Main Authors: Chandra, Aditi, Yoon, Sora, Michieletto, Michaël F., Goldman, Naomi, Ferrari, Emily K., Abedi, Maryam, Johnson, Isabelle, Fasolino, Maria, Pham, Kenneth, Joannas, Leonel, Kee, Barbara L., Henao-Mejia, Jorge, Vahedi, Golnaz
• Format: Article
• Language: English
• Subjects: 3D genome organization; allergic inflammation; allergy; Animals; asthma; CD4 T helper differentiation; Cell Differentiation - genetics; colitis; dosage control; Enhancer Elements, Genetic - genetics; ETS1; Hematopoiesis; Humans; Hypersensitivity - genetics; Inflammation - genetics; Mice; multi-enhancer hubs; Regulatory Sequences, Nucleic Acid; T-Lymphocytes; transcription factor
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2023.05.004

Multi-enhancer hubs are spatial clusters of enhancers present across numerous developmental programs. Here, we studied the functional relevance of these three-dimensional structures in T cell biology. Mathematical modeling identified a highly connected multi-enhancer hub at the Ets1 locus, comprising a noncoding regulatory element that was a hotspot for sequence variation associated with allergic disease in humans. Deletion of this regulatory element in mice revealed that the multi-enhancer connectivity was dispensable for T cell development but required for CD4+ T helper 1 (Th1) differentiation. These mice were protected from Th1-mediated colitis but exhibited overt allergic responses. Mechanistically, the multi-enhancer hub controlled the dosage of Ets1 that was required for CTCF recruitment and assembly of Th1-specific genome topology. Our findings establish a paradigm wherein multi-enhancer hubs control cellular competence to respond to an inductive cue through quantitative control of gene dosage and provide insight into how sequence variation within noncoding elements at the Ets1 locus predisposes individuals to allergic responses. [Display omitted] •Ets1 locus forms a multi-enhancer hub containing a super-enhancer called Ets1-SE•Ets1-SE is required for Th1 differentiation and the Ets1 gene dosage control•Deletion of Ets1-SE leads to protection against colitis and an overt allergic response•Ets1 dosage controls the Th1-specific genome topology through the recruitment of CTCF Multi-enhancer hubs are spatial clusters of enhancers present across numerous developmental programs. Chandra, Yoon, Michieletto, et al. examine the functional relevance of multi-enhancer hubs in T cell biology and show that the multiplicity of enhancers interacting with the Ets1 gene is essential to control the precise dosage of Ets1 in response to cytokine cues, and the failure to do so can lead to allergic diseases.