Neuroprotective protein ADNP-dependent histone remodeling complex promotes T helper 2 immune cell differentiation

Type 2 immune responses are critical in tissue homeostasis, anti-helminth immunity, and allergy. T helper 2 (Th2) cells produce interleukin-4 (IL-4), IL-5, and IL-13 from the type 2 gene cluster under regulation by tran-scription factors (TFs) including GATA3. To better understand transcriptional regulation of Th2 cell differen-tiation, we performed CRISPR-Cas9 screens targeting 1,131 TFs. We discovered that activity-dependent neuroprotector homeobox protein (ADNP) was indispensable for immune reactions to allergen. Mechanisti-cally, ADNP performed a previously unappreciated role in gene activation, forming a critical bridge in the tran-sition from pioneer TFs to chromatin remodeling by recruiting the helicase CHD4 and ATPase BRG1. Although GATA3 and AP-1 bound the type 2 cytokine locus in the absence of ADNP, they were unable to initiate histone acetylation or DNA accessibility, resulting in highly impaired type 2 cytokine expression. Our results demonstrate an important role for ADNP in promoting immune cell specialization.

Automated summary

The study found that ADNP plays an indispensable role in immune reactions to allergens by recruiting proteins such as CHD4 and BRG1, serving as a critical bridge in gene activation and promoting T cell differentiation. The absence of ADNP impairs the ability of GATA3 and AP-1 to initiate histone acetylation and DNA accessibility, resulting in impaired expression of type 2 cytokines. These results demonstrate the importance of ADNP in promoting immune cell specialization.