Fat mass and obesity-associated protein regulates RNA methylation associated with spatial cognitive dysfunction after chronic cerebral hypoperfusion.

RNA methylation can epigenetically regulate learning and memory. However, it is unclear whether RNA methylation plays a critical role in the pathophysiology of Vascular dementia (VD). Here, we report that expression of the fat mass and obesity associated gene (FTO), an RNA demethylase, is downregulated in the hippocampus in models of VD. Through prediction and dual-luciferase reporters validation studies, we observed that miRNA-711 was upregulated after VD and could bind to the 3'-untranslated region of FTO mRNA and regulate its expression in vitro. Methylated RNA immunoprecipitation (MeRIP)-qPCR assay and functional study confirmed that Syn1 was an important target gene of FTO. This suggests that FTO is an important regulator of Syn1. FTO upregulation by inhibition of miR-711 in the hippocampus relieves synaptic association protein and synapse deterioration in vivo, whereas FTO downregulation by miR-711 agomir in the hippocampus leads to aggravate the synapse deterioration. FTO upregulation by inhibition of miR-711 relieves cognitive impairment of rats VD model, whereas FTO downregulation by miR-711 deteriorate cognitive impairment. Our findings suggest that FTO is a regulator of a mechanism underlying RNA methylation associated with spatial cognitive dysfunction after chronic cerebral hypoperfusion.

Nsun2 coupling with RoRγt shapes the fate of Th17 cells and promotes colitis.

T helper 17 (Th17) cells are a subset of CD4+ T helper cells involved in the inflammatory response in autoimmunity. Th17 cells secrete Th17 specific cytokines, such as IL-17A and IL17-F, which are governed by the master transcription factor RoRγt. However, the epigenetic mechanism regulating Th17 cell function is still not fully understood. Here, we reveal that deletion of RNA 5-methylcytosine (m5C) methyltransferase Nsun2 in mouse CD4+ T cells specifically inhibits Th17 cell differentiation and alleviates Th17 cell-induced colitis pathogenesis. Mechanistically, RoRγt can recruit Nsun2 to chromatin regions of their targets, including Il17a and Il17f, leading to the transcription-coupled m5C formation and consequently enhanced mRNA stability. Our study demonstrates a m5C mediated cell intrinsic function in Th17 cells and suggests Nsun2 as a potential therapeutic target for autoimmune disease.

N6-methyladenosine RNA modification suppresses antiviral innate sensing pathways via reshaping double-stranded RNA.

Double-stranded RNA (dsRNA) is a virus-encoded signature capable of triggering intracellular Rig-like receptors (RLR) to activate antiviral signaling, but whether intercellular dsRNA structural reshaping mediated by the N6-methyladenosine (m6A) modification modulates this process remains largely unknown. Here, we show that, in response to infection by the RNA virus Vesicular Stomatitis Virus (VSV), the m6A methyltransferase METTL3 translocates into the cytoplasm to increase m6A modification on virus-derived transcripts and decrease viral dsRNA formation, thereby reducing virus-sensing efficacy by RLRs such as RIG-I and MDA5 and dampening antiviral immune signaling. Meanwhile, the genetic ablation of METTL3 in monocyte or hepatocyte causes enhanced type I IFN expression and accelerates VSV clearance. Our findings thus implicate METTL3-mediated m6A RNA modification on viral RNAs as a negative regulator for innate sensing pathways of dsRNA, and also hint METTL3 as a potential therapeutic target for the modulation of anti-viral immunity.