Low Expression of YTH Domain-Containing 1 Promotes Microglial M1 Polarization by Reducing the Stability of Sirtuin 1 mRNA

Frontiers in Cellular Neuroscience

卷:15

Shengping Hou¹  Shiyun Tang¹  Zongren Xu¹  Hongxiu Zhou¹  Xingyun Liao¹  Na Li⁴ 

[1] Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, China;

[2] Chongqing Eye Institute, Chongqing, China;

[3] Chongqing Key Laboratory of Ophthalmology, Chongqing, China;

[4] College of Basic Medicine, Chongqing Medical University, Chongqing, China;

[5] The First Affiliated Hospital of Chongqing Medical University, Chongqing, China;

关键词: m6A;    YTHDC1;    microglia cells;    SIRT1;    RNA stability;   

DOI  :  10.3389/fncel.2021.774305

来源: DOAJ

【 摘 要 】

The N6-methyladenosine (m6A) modification is the most abundant posttranscriptional mRNA modification in mammalian cells and is dynamically modulated by a series of “writers,” “erasers,” and “readers.” Studies have shown that m6A affects RNA metabolism in terms of RNA processing, nuclear export, translation, and decay. However, the role of the m6A modification in retinal microglial activation remains unclear. Here, we analyzed the single-cell RNA sequencing data of retinal cells from mice with uveitis and found that the m6A-binding protein YTH domain-containing 1 (YTHDC1) was significantly downregulated in retinal microglia in the context of uveitis. Further studies showed that YTHDC1 deficiency resulted in M1 microglial polarization, an increased inflammatory response and the promotion of microglial migration. Mechanistically, YTHDC1 maintained sirtuin 1 (SIRT1) mRNA stability, which reduced signal transducer and activator of transcription 3 (STAT3) phosphorylation, thus inhibiting microglial M1 polarization. Collectively, our data show that YTHDC1 is critical for microglial inflammatory response regulation and can serve as a target for the development of therapeutics for autogenic immune diseases.

【 授权许可】

Unknown