Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH.
Proc Natl Acad Sci U S A. 2024 Apr 23;121(17):e2320938121. doi: 10.1073/pnas.2320938121. Epub 2024 Apr 18.
The MYC-Associated Zinc Finger Protein (MAZ) plays important roles in chromatin organization and gene transcription regulation. Dysregulated expression of MAZ causes diseases, such as glioblastoma, breast cancer, prostate cancer, and liposarcoma. Previously, it has been reported that MAZ controls the proinflammatory response in colitis and colon cancer via STAT3 signaling, suggesting that MAZ is involved in regulating immunity-related pathways. However, the molecular mechanism underlying this regulation remains elusive. Here, we investigate the regulatory effect of MAZ on interferon-gamma (IFN-γ)-stimulated genes via STAT1, a protein that plays an essential role in immune responses to viral, fungal, and mycobacterial pathogens. We demonstrate that about 80% of occupied STAT1-binding sites colocalize with occupied MAZ-binding sites in HAP1/K562 cells after IFNγ stimulation. MAZ depletion significantly reduces STAT1 binding in the genome. By analyzing genome-wide gene expression profiles in the RNA-Seq data, we show that MAZ depletion significantly suppresses a subset of the immune response genes, which include the IFN-stimulated genes IRF8 and Absent in Melanoma 2. Furthermore, we find that MAZ controls expression of the immunity-related genes by changing the epigenetic landscape in chromatin. Our study reveals an important role for MAZ in regulating immune-related gene expression.
MAZ（MYC 相关锌指蛋白）在染色质组织和基因转录调控中发挥重要作用。MAZ 表达失调会导致疾病，如脑胶质瘤、乳腺癌、前列腺癌和脂肪肉瘤。先前的研究表明，MAZ 通过 STAT3 信号通路控制结肠炎和结肠癌中的促炎反应，这表明 MAZ 参与调节与免疫相关的通路。然而，这种调节的分子机制尚不清楚。在这里，我们研究了 MAZ 通过 STAT1（一种在抗病毒、真菌和分枝杆菌病原体的免疫反应中起关键作用的蛋白质）对干扰素-γ（IFN-γ）刺激基因的调节作用。我们证明，在 IFNγ 刺激后，大约 80%的被 STAT1 结合的位点与 HAP1/K562 细胞中被 MAZ 结合的位点共定位。MAZ 缺失显著减少了基因组中的 STAT1 结合。通过分析 RNA-Seq 数据中的全基因组基因表达谱，我们表明 MAZ 缺失显著抑制了一组免疫反应基因，其中包括 IFN 刺激基因 IRF8 和黑色素瘤 2 缺失。此外，我们发现 MAZ 通过改变染色质中的表观遗传景观来控制免疫相关基因的表达。我们的研究揭示了 MAZ 在调节免疫相关基因表达中的重要作用。
