Martinez John C, Morandini Francesco, Fitzgibbons Lucinda, Sieczkiewicz Natasha, Bae Sung Jae, Meadow Michael E, Hillpot Eric, Cutting Joseph, Paige Victoria, Biashad Seyed Ali, Simon Matthew, Sedivy John, Seluanov Andrei, Gorbunova Vera
Translational Biomedical Sciences Program, University of Rochester, NY, 14627, USA.
Department of Biology, University of Rochester, NY, 14627, USA.
bioRxiv. 2024 Oct 11:2024.10.10.617645. doi: 10.1101/2024.10.10.617645.
Aging-associated inflammation, or 'inflammaging" is a driver of multiple age-associated diseases. Cyclic GMP-AMP Synthase (cGAS) is a cytosolic DNA sensor that functions to activate interferon response upon detecting viral DNA in the cytoplasm. cGAS contributes to inflammaging by responding to endogenous signals such as damaged DNA or LINE1 (L1) cDNA which forms in aged cells. While cGAS knockout mice are viable their aging has not been examined. Unexpectedly, we found that cGAS knockout mice exhibit accelerated aging phenotype associated with induction of inflammation. Transcription of L1 elements was increased in both cGAS knockout mice and in cGAS siRNA knockdown cells associated with high levels of cytoplasmic L1 DNA and expression of ORF1 protein. Cells from cGAS knockout mice showed increased chromatin accessibility and decreased DNA methylation on L1 transposons. Stimulated emission depletion microscopy (STED) showed that cGAS forms nuclear condensates that co-localize with H3K9me3 heterochromatin marks, and H3K9me3 pattern is disrupted in cGAS knockout cells. Taken together these results suggest a previously undescribed role for cGAS in maintaining heterochromatin on transposable elements. We propose that loss of cGAS leads to loss of chromatin organization, de-repression of transposable elements and induction of inflammation resulting in accelerated aging.
与衰老相关的炎症，即“炎症衰老”，是多种与年龄相关疾病的驱动因素。环鸟苷酸-腺苷酸合成酶（cGAS）是一种胞质DNA传感器，其功能是在检测到细胞质中的病毒DNA时激活干扰素反应。cGAS通过对诸如受损DNA或衰老细胞中形成的LINE1（L1）cDNA等内源性信号作出反应，从而导致炎症衰老。虽然cGAS基因敲除小鼠可以存活，但尚未对其衰老情况进行研究。出乎意料地，我们发现cGAS基因敲除小鼠表现出与炎症诱导相关的加速衰老表型。在cGAS基因敲除小鼠和cGAS siRNA敲低细胞中，L1元件的转录均增加，这与高水平的细胞质L1 DNA和ORF1蛋白的表达相关。来自cGAS基因敲除小鼠的细胞显示出染色质可及性增加以及L1转座子上的DNA甲基化减少。受激发射损耗显微镜（STED）显示，cGAS形成与H3K9me3异染色质标记共定位的核凝聚物，并且在cGAS基因敲除细胞中H3K9me3模式被破坏。综合这些结果表明，cGAS在维持转座元件上的异染色质方面具有先前未描述的作用。我们提出，cGAS的缺失导致染色质组织的丧失、转座元件的去抑制和炎症的诱导，从而导致加速衰老。
