Unravelling the role of ZNF341 in HIES, STAT3 GOF and STAT1 GOF-related inborn errors of immunity

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2022

Inborn errors of immunity represent a wide group of congenital diseases that cause abnormal functioning of the immune system and more susceptibility to infections. Hyper IgE syndrome (HIES) is caused by genetic mutations in several genes among which the transcription factors STAT1 and STAT3, which regulate many aspects of cellular immunity, proliferation, apoptosis and differentiation. Recently, another transcription factor, ZNF341, has been described as causative of HIES. ZNF341 binds to STAT3 promoter and positively regulates its expression. Therefore, ZNF341-deficient patients present lower levels of STAT3 expression and consequently manifest the disease. However, the interplay between ZNF341 and STAT molecules appears to be more complicated than expected because also STAT1 and STAT3 bind to ZNF341 promoters, suggesting cross-regulation mechanisms with unknown roles in HIES and related disorders. A broad multidisciplinary approach will be employed combining expertise in medical genetics, cutting-edge next generation sequencing methods, cellular and molecular biology, and animal models. This project aims to study the role of ZNF341 in patients with mutations in STAT1 and STAT3, to elucidate the molecular mechanisms underlying the pathology. In addition, the use of mouse models will allow a detailed understanding of the functioning of ZNF341 and its relationships with STATs. Moreover, enrollment of patients with HIES-related diseases may help identify additional causes of these inborn errors of immunity. Altogether, results of this study will provide novel insights into the general understanding of HIES and related disorders, leading to the identification of risk factors and biomarkers needed to design preventive and therapeutic approaches.