Function and impact of the transcription factor ZNF341 in lymphocytes

淋巴细胞转录因子 ZNF341 的功能和影响

• 批准号: 519635399
• 负责人: Professor Dr. Bodo Grimbacher
• 金额: --
• 依托单位: Centrum für Chronische Immundefizienz (CCI)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/519635399?language=en
• 关键词: Function; impact; transcription; factor; ZNF341

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.

信号转导子和转录激活子3（STAT 3）是免疫稳态的中心调节因子。STAT 3水平受到严格控制，并且STAT 3损伤有助于几种疾病，包括单基因常染色体显性高免疫球蛋白E（IgE）综合征（AD-HIES），其特征在于复发性和严重的皮肤和鼻窦细菌感染、慢性皮炎以及血清IgE升高和结缔组织异常。锌指转录因子ZNF 341已被鉴定为STAT 3的调节因子，因为ZNF 341中具有纯合无义突变的患者呈现与HIES患者相似的特征。野生型ZNF 341结合并激活STAT 3启动子，而突变变体显示转录激活受损，部分原因是核转位失败。ZNF 341患者的细胞具有较低的STAT 3 mRNA和蛋白的基础水平，并且在细胞被特定细胞因子激活后，STAT 3磷酸化强烈受损。与STAT 3显性失活突变患者一样，ZNF 341缺陷患者缺乏辅助性T细胞17（Th 17），并表现出受影响的Th 17分化。因此，STAT 3已被鉴定为转录因子ZNF 341的主要靶基因，导致STAT 3水平不足，因此在具有纯合ZNF 341突变的患者中具有STAT 3样表型。为了破译ZNF 341突变引起的分子缺陷以及对其他靶基因调节的影响，需要对静息细胞和细胞因子刺激下的表达谱进行详细分析。因此，我们在本项目中建议通过鉴定ZNF 341相互作用伙伴、通过验证潜在靶基因分析ZNF 341转录活性以及在染色质水平评估ZNF 341转录活性来研究ZNF 341的功能。最后，我们将通过分析ZNF 341的表达是如何调节的以及ZNF 341依赖性STAT 3和STAT 1信号转导在多大程度上受到细胞因子刺激的影响来研究ZNF 341的调节。因此，通过这一提议，我们希望破译ZNF 341在淋巴细胞中的生物学作用，这将有助于未来开发ZNF 341突变患者的潜在治疗方法。