Function and impact of the transcription factor ZNF341 in lymphocytes

• Applicant: Professor Dr. Bodo Grimbacher
• Subject Area: Immunology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 519635399

Signal transducer and activator of transcription 3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled, and STAT3 impairment contributes to several diseases including the monogenic autosomal-dominant hyper–immunoglobulin E (IgE) syndrome (AD-HIES), characterized by recurrent and severe cutaneous and sinopulmonary bacterial infections, chronic dermatitis, and elevated serum IgE and connective tissue abnormalities. The zinc finger transcription factor ZNF341, has been identified as a regulator of STAT3, since patients with homozygous nonsense mutations in ZNF341, present similar characteristics to HIES patients. Wild-type ZNF341 bound to and activates the STAT3 promoter, whereas the mutant variants shows impaired transcriptional activation, partly due to nuclear translocation failure. ZNF341 patients´ cells have lower basal levels of STAT3 mRNA and protein, and STAT3 phosphorylation is strongly impaired after cells are activated with specific cytokines. Like patients with STAT3 dominant negative mutations, ZNF341-deficient patients lack T helper 17 (Th17) cells, and show affected Th17 differentiation. Therefore, STAT3 has been identified as a main target gene of the transcription factor ZNF341, resulting in insufficient STAT3 levels and therefore a STAT3-like phenotype in patients with homozygous ZNF341 mutations. To decipher the molecular defects caused by ZNF341 mutations and the effects on the regulation of additional target genes, a detailed analysis of the expression profile, in resting cells and under cytokine stimulation, is required. Thereby, we propose in this project to study the function of the transcription factor ZNF341 by identifying ZNF341 interaction partners, analyzing ZNF341 transcriptional activity by validating potential target genes and evaluating ZNF341 transcriptional activity at the chromatin level. Finally we will study ZNF341 regulation by the analysis of how ZNF341 expression is regulated and to which extent ZNF341-dependent STAT3 and STAT1 signaling can be influenced by cytokine stimulation. Therefore, with this proposal we expect to decipher the biological role of ZNF341 in lymphocytes, which it will help to develop in the future, potential therapies to patients with ZNF341 mutations.

• DFG Programme: Research Grants