Takai Jun, Ueki Hinata, Uemura Satoshi
Faculty of Medicine, Division of Medical Biochemistry, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan.
Faculty of Medicine, Division of Medical Biochemistry, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan.
J Biol Chem. 2025 Jun 16;301(7):110372. doi: 10.1016/j.jbc.2025.110372.
Kidney diseases pose a medical challenge worldwide. Excessive kidney inflammation plays a central role in disease progression. While the transcription factor GATA binding protein 2 (GATA2) is known to govern the hematopoietic system, emerging evidence suggests that it also promotes kidney inflammation. To date, the precise molecular mechanisms underlying GATA2-mediated kidney inflammation remain unclear. Here, we examined the transcriptional landscape, genome-wide GATA2 occupancy, and chromatin accessibility upon GATA2 induction in kidney cells. We generated an inducible GATA2 expression system using a renal tubular cell line and then performed RNA-seq, Assay for Transposase-Accessible Chromatin (ATAC)-seq, and Cleavage Under Targets and Tagmentation (CUT&Tag). We also conducted ATAC-seq using GATA2-expressing cell fractions sorted from mouse kidney tissues. These comprehensive analyses demonstrated that GATA2 directly upregulates genes associated with kidney inflammation. In particular, GATA2 bound to crucial kidney inflammation-associated gene loci and increased chromatin accessibility at these regions, including colony-stimulating factor 1 (Csf1), C-X-C motif chemokine ligand 10 (Cxcl10), and vascular cell adhesion molecule-1 (Vcam1). Motif analysis revealed that the binding sequences of the activator protein-1 (AP-1), an inflammation-induced transcription factor, are frequently located adjacent to genomic regions where GATA2 increases chromatin accessibility. Furthermore, the upregulation of Csf1, Cxcl10, and Vcam1 following GATA2 induction was attenuated by the AP-1-specific inhibitor T-5224. Overall, this study is the first to determine genome-wide GATA2 occupancy and its impact on chromatin accessibility in kidney cells. These findings provide molecular insights into the role of GATA2 in kidney inflammation.
肾脏疾病在全球范围内构成了医学挑战。过度的肾脏炎症在疾病进展中起着核心作用。虽然已知转录因子GATA结合蛋白2（GATA2）调控造血系统，但新出现的证据表明它也促进肾脏炎症。迄今为止，GATA2介导的肾脏炎症的确切分子机制仍不清楚。在这里，我们研究了肾脏细胞中GATA2诱导后的转录图谱、全基因组GATA2占位情况以及染色质可及性。我们使用肾小管细胞系构建了一个可诱导的GATA2表达系统，然后进行了RNA测序、转座酶可及染色质分析（ATAC-seq）和靶向切割与标签化（CUT&Tag）。我们还使用从小鼠肾脏组织中分选的表达GATA2的细胞组分进行了ATAC-seq。这些综合分析表明，GATA2直接上调与肾脏炎症相关的基因。特别是，GATA2与关键的肾脏炎症相关基因位点结合，并增加了这些区域的染色质可及性，包括集落刺激因子1（Csf1）、C-X-C基序趋化因子配体10（Cxcl10）和血管细胞黏附分子-1（Vcam1）。基序分析显示，炎症诱导的转录因子激活蛋白-1（AP-1）的结合序列经常位于GATA2增加染色质可及性的基因组区域附近。此外，AP-1特异性抑制剂T-5224减弱了GATA2诱导后Csf1、Cxcl10和Vcam1的上调。总体而言，本研究首次确定了全基因组GATA2占位及其对肾脏细胞染色质可及性的影响。这些发现为GATA2在肾脏炎症中的作用提供了分子见解。
