PO.MCB07.03 · 分子与细胞生物学
MYC与KDM7A协作抑制SIDT2并削弱dsRNA介导的抗肿瘤免疫
MYC cooperatives with KDM7A to repress SIDT2 and dampens dsRNA-mediated anti-tumor immunity
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
MYC是一种在多种癌症中频繁扩增的原癌基因，因其转录激活功能而广为人知，然而MYC介导转录抑制的机制仍知之甚少。通过整合多组学分析，我们鉴定出SIDT2是一个受MYC抑制的新型直接靶标。对公共单细胞RNA测序数据集的分析揭示MYC与SIDT2之间存在互斥的表达模式，且它们的表达水平在多个肿瘤转录组数据集中呈负相关。SIDT2的缺失降低了胞质双链RNA（dsRNA）水平，导致包括CXCL9、CXCL10、CXCL11和CCL5在内的炎性趋化因子表达减少，从而损害T细胞募集。抑制DDX58和IFIH1这两个对固有免疫信号传导至关重要的dsRNA传感器，可消除SIDT2缺失所导致的细胞因子减少，表明SIDT2依赖的细胞因子表达是通过dsRNA通路介导的。与其功能作用一致，SIDT2表达与细胞毒性T淋巴细胞浸润呈正相关，并与接受免疫检查点阻断治疗患者的良好结局相关。为鉴定促进MYC介导转录抑制的因子，我们检查了直接被MYC结合并抑制的基因，发现其与组蛋白去甲基化酶KDM7A调控的基因靶标有大量重叠。从机制上讲，KDM7A作为一种转录辅因子，使MYC能够抑制SIDT2的转录。MYC和KDM7A共同占据SIDT2的调控区域，形成一个协作性的抑制复合物，而KDM7A的缺失则消除了MYC依赖的SIDT2下调。ATAC-seq分析进一步支持了这一机制，显示MYC敲低显著增加SIDT2位点的染色质可及性，而当KDM7A被抑制或耗竭时这种染色质重塑则不会发生，表明KDM7A对于维持MYC施加的抑制性染色质状态至关重要。总之，这些发现揭示了一种此前未被认识的MYC-KDM7A协作机制，该机制沉默SIDT2，为MYC介导的转录抑制提供了机制基础，并阐明了致癌MYC如何抑制dsRNA驱动的抗肿瘤免疫反应。
查看英文原文 English abstract
MYC is a proto-oncogene frequently amplified in various cancers and is well known for its transcriptional activation functions, yet the mechanisms by which MYC mediates transcriptional repression remain poorly understood. Through integrative multi-omics analysis, we identified SIDT2 as a novel direct target repressed by MYC. Analysis of public single-cell RNA sequencing datasets revealed mutually exclusive expression patterns between MYC and SIDT2 , and their expression levels were inversely correlated across tumor transcriptome datasets. Loss of SIDT2 reduced cytoplasmic double-stranded RNA (dsRNA) levels, leading to decreased expression of inflammatory chemokines including CXCL9 , CXCL10 , CXCL11 and CCL5 , resulting in impaired T cell recruitment. Inhibition of DDX58 and IFIH1 , two dsRNA sensors essential for innate immune signaling, abrogated the cytokine reduction caused by SIDT2 loss, demonstrating that SIDT2 -dependent cytokine expression is mediated through the dsRNA pathway. Consistent with its functional role, SIDT2 expression correlated positively with cytotoxic T lymphocyte infiltration and was associated with favorable outcomes in patients receiving immune checkpoint blockade therapy. To identify factors that facilitate MYC-mediated transcriptional repression, we examined genes directly bound and suppressed by MYC and found substantial overlaps with gene targets regulated by KDM7A, a histone demethylase. Mechanistically, KDM7A functions as a transcriptional cofactor that enables MYC to repress SIDT2 transcription. MYC and KDM7A co-occupied the regulatory region of SIDT2 , forming a cooperative repressive complex, and loss of KDM7A abolishes MYC-dependent downregulation of SIDT2 . ATAC-seq analysis further supported this mechanism by showing that MYC knockdown markedly increases chromatin accessibility at the SIDT2 locus, whereas this chromatin remodeling does not occur when KDM7A is inhibited or depleted, indicating that KDM7A is essential for maintaining the repressive chromatin state imposed by MYC. Together, these findings reveal a previously unrecognized MYC-KDM7A cooperative mechanism that silences SIDT2 , providing a mechanistic basis for MYC-mediated transcriptional repression and clarifying how oncogenic MYC suppresses dsRNA-driven anti-tumor immune responses.
利益披露 Disclosure
T. Lee, None..
K. Lee, None..
S. Son, None.