PO.BCS01.01 · 生物信息与计算
体细胞NFKBIZ变异在单细胞分辨率下调节炎症
Somatic NFKBIZ v ariant modulates inflammation at single-cell resolution
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
人体是一个体细胞嵌合体，正常组织被携带不同突变的细胞群落所定植。有趣的是，在受慢性疾病影响的组织中，如炎症性肠病（IBD），出现了疾病特异性的克隆扩增驱动因子。IBD以慢性肠道炎症和癌症风险增加为特征。这种炎症环境施加选择压力，促进携带IL-17炎症通路基因体细胞突变的克隆生长。虽然许多此类突变已被认为可下调炎症并抵御结肠炎相关结直肠癌，但其存在尚未在实体人类组织中以单细胞分辨率得到表征。我们使用SComatic在来自IBD患者（n=204）的单细胞RNA测序结直肠样本中鉴定体细胞单核苷酸变异。其中，我们发现了NFKBIZ锚蛋白重复结构域中一个新的错义突变，预测其具有高度致病性，该结构域对IL-17通路中的启动子结合至关重要。NFKBIZ是肠道炎症的关键调节因子，也是IBD中已知的克隆扩增驱动因子。值得注意的是，虽然NFKBIZ变异在IBD中高度普遍，但在结肠炎相关癌症中却很少发现，提示这种在慢性炎症组织中的适应对癌症具有保护作用。引人注目的是，我们发现该变异仅出现在上皮细胞中。在这一区室中，它表现出0.727的高变异等位基因频率，提示在慢性炎症期间结肠上皮发生了大量重塑。在功能上，该变异似乎破坏了IL-17介导的信号，因为其存在与DUOX2（一个已知的IL-17靶基因，可引起DNA损伤并在IBD结肠炎症中频繁上调）表达降低相关。这首次在天然人类组织中以单细胞分辨率展示了此前假设的由体细胞NFKBIZ突变驱动的保护机制。我们的工作揭示了保护性克隆如何在特定细胞类型中应对慢性炎症而出现，凸显了上皮重塑如何影响IBD疾病进展和治疗反应。
查看英文原文 English abstract
The human body is a somatic mosaic, with normal tissue colonized by cell populations carrying distinct mutations. Intriguingly, in tissues affected by chronic disease, such as inflammatory bowel disease (IBD), disease-specific drivers of clonal expansion emerge. IBD is characterized by chronic intestinal inflammation and increased cancer risk. This inflammatory environment exerts selective pressure promoting the growth of clones carrying somatic mutations in IL-17 inflammatory pathway genes. While many such mutations have been implicated in downregulating inflammation and protecting against colitis-associated colorectal cancer, their presence has yet to be characterized at single-cell resolution in solid human tissue. We used SComatic to identify somatic single nucleotide variants in single-cell RNA-sequenced colorectal samples from IBD patients ( n =204). Among them, we found a novel missense mutation predicted to be highly pathogenic in the ankyrin repeat domain of NFKBIZ , which is critical for promoter binding in the IL-17 pathway. NFKBIZ is a key regulator of intestinal inflammation and a known driver of clonal expansion in IBD. Notably, while NFKBIZ variants are highly prevalent in IBD, they are rarely found in colitis-associated cancer, suggesting this adaptation in chronically inflamed tissue is protective against cancer. Strikingly, we found that the variant appears exclusively in epithelial cells. In this compartment, it exhibited a high variant allele frequency of 0.727, suggesting substantial remodeling of colonic epithelium during chronic inflammation. Functionally, the variant appeared to disrupt IL-17-mediated signaling, as its presence was associated with reduced expression of DUOX2 , a known IL-17 target gene that causes DNA damage and is frequently upregulated in colonic inflammation in IBD. This shows, for the first time at single-cell resolution in native human tissue, previously hypothesized protective mechanisms driven by somatic NFKBIZ mutations. Our work reveals how protective clones emerge in specific cell types in response to chronic inflammation, highlighting how epithelial remodeling can influence IBD disease progression and treatment response.
利益披露 Disclosure
C. H. Feng, None..
A. R. D'Avino, None..
A. W. Rasmussen, None.