Heterochromatin inhibits cGAS and STING during oxidative stress-induced retinal pigment epithelium and retina degeneration

• Published in: Free radical biology & medicine 2022-01, Vol.178, p.147-160
• Main Authors: Zou, Ming, Gong, Lili, Ke, Qin, Qi, Ruili, Zhu, Xingfei, Liu, Wei, Sun, Qian, Tang, Xiangcheng, Luo, Zhongwen, Gong, Xiaodong, Liu, Yizhi, Li, David Wan-Cheng
• Format: Article
• Language: English
• Subjects: Age-related macular degeneration; Animals; cGAS; Heterochromatin; Heterochromatin - genetics; Humans; Inflammation; Membrane Proteins - metabolism; Methotrexate; Mice; Nucleotidyltransferases - metabolism; Oxidative Stress; Retina; Retinal Pigment Epithelium; STING
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2021.11.040

Age-related macular degeneration (AMD) is a leading cause of blindness characterized by degeneration of retina pigment epithelium (RPE) and photoreceptors in the macular region. Activation of the innate immune cGAS-STING signaling has been detected in RPE of dry AMD patients, but the regulatory basis is largely unexplored. Heterochromatin is a highly compact, transcription inert chromatin status. We have recently shown that heterochromatin is required for RPE survival through epigenetically silencing p53-mediated apoptosis signaling. Here, we found that cGAS and STING were dose-dependently upregulated in mouse RPE and retina during oxidative injury, correlated with decreased chromatin compaction in their gene loci. Genetic or pharmaceutical disruption of heterochromatin leads to elevated cGAS and STING expression and enhanced inflammatory response in oxidative stress-induced RPE and retina degeneration. In contrast, application of methotrexate (MTX), a recently identified heterochromatin-promoting drug, inhibits cGAS and STING in both RPE and retina, attenuates RPE/retina degeneration and inflammation. Further, we show that intact heterochromatin is required for MTX to repress cGAS and STING. Together, we demonstrated an unrevealed regulatory function of heterochromatin on cGAS and STING expression and provide potential new therapeutic strategy for AMD treatment. Our in silico analysis reveals increased STING chromatin accessibility and transcription in macular RPE of dry AMD patients. Heterochromatin, which is constructed by H3K9me3 mark and HP1α protein, inhibits cGAS and STING, and thus suppresses RPE and retina inflammation upon oxidative injury. [Display omitted] •In silico analysis shows increased STING chromatin accessibility and transcription in macular RPE of dry AMD patients.•Oxidative stress (OS) induces cGAS and STING in mouse RPE and retina in a dose-dependent manner, correlating with progressive RPE and retina degeneration.•OS causes increased cGAS and STING chromatin accessibility, whereas disruption of compact heterochromatin enhances cGAS-STING inflammatory reaction in RPE and retina.•Methotrexate promotes heterochromatin formation on cGAS and STING promoters, represses cGAS-SITNG signaling and retina cell death upon OS exposure.