时间标签：数据日期 2026-11-05 · 生成时间 2026-11-05 05:30（Asia/Shanghai）｜ 检索窗口 PubMed edat 2026/11/02 – 2026/11/06 ｜ 情报发生日期 2026-11-05
研究问题
Given the reported high-affinity binding of cGAS to nucleosomes (15–20), we asked whether chromatin-associated cGAS regulates 3D genome architecture.；Micro-C analysis of empty vector–reconstituted (EV-reconstituted) and WT-cGAS–reconstituted cells revealed no appreciable differences in chromatin organization (Figure 1B and Supplemental Figure 1K), suggesting that cGAS does not substantially regulate 3D chromatin architecture.Given that nuclear cGAS has functions beyond innate immunity, including inhibition of PARP1-mediated DNA repair (21), regulation of replication fork progression (7), and centromere binding (8), we asked whether chromatin-associated cGAS regulates transcription.；These distinct states are explored below.Integrative CUT&RUN, RNA-seq, and nuclear cGAS TurboID analyses reveal that cGAS interacts with AP-1 transcription factors to regulate genes involved in cholesterol homeostasis.To determine whether non-nucleosomal chromatin-associated cGAS regulates transcription, we performed RNA-seq in EV-, WT-cGAS–, and KKEA-cGAS–expressing MDA-MB-231 cGAS−/− cells (Figure 3A).
方法
We therefore hypothesized that chromatin-associated cGAS may have functions beyond immune sensing.；Using CUT&RUN with cGAS mutants defective in DNA binding (KKEA) or nucleosome binding (R255E), we found that most chromatin-associated cGAS is neither tethered to nucleosomes nor dependent on DNA binding.；We generated cGAS−/− MDA-MB-231 cells and reconstituted them with WT or DNA-binding–deficient KKEA-cGAS (Supplemental Figure 1H).
核心结论
Collectively, these mechanisms prevent inappropriate cGAS activation in the DNA-rich nucleus.It may seem counterintuitive for cells to sequester a substantial fraction of cGAS in chromatin, particularly given the lack of evidence that nuclear cGAS is acutely mobilized to the cytoplasm upon DNA virus infection.；Using CUT&RUN with cGAS mutants defective in DNA binding (KKEA) or nucleosome binding (R255E), we found that most chromatin-associated cGAS is neither tethered to nucleosomes nor dependent on DNA binding.；These findings suggest 3 potential chromatin-associated states of cGAS: nucleosome-tethered, nucleosome- and transcription factor–associated, and transcription factor/chromatin remodeler–associated (Figure 2D).
局限
However, high-confidence true-cGAS peaks were detected at the LGALS3, but not PPARG, locus (Figure 3D and Supplemental Figure 2C).；However, unlike 4FA, the F491A/F503A mutant retained DNA-induced cGAS activation (Figure 5, E and F).；Thus, cGas–/– mice do not exhibit overt pulmonary inflammation or pathology under basal conditions at 4 months of age, despite reduced Lgals3 expression.However, under the stress of CO2 euthanasia, cGas–/– lungs appeared visibly enlarged, whereas the liver, heart, kidney, spleen, and overall body weight were unchanged (Supplemental Figure 10, A–K).
对本项目的价值
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全文来源
PubMed PMC JATS（正文 56,108 字符，题名指纹 0.75，已过 PubMed PMCID 官方关联 + 题名指纹 + 正文长度归属校验）
原文题录
- 中文题名：核内 cGAS 调控转录以控制脂代谢、肿瘤生长与治疗应答
- 英文标题：Nuclear cGAS governs transcription to control lipid metabolism, tumor growth, and therapy response.
- 期刊与标识：The Journal of clinical investigation · PMID 42969224 · DOI 10.1172/JCI205579 · PMC PMC13722394