No abstract

N6-methyladenosine (m6A) RNA methylation is the most abundant modification on mRNAs and plays important roles in various biological processes. The formation of m6A is catalyzed by a methyltransferase complex including methyltransferase-like 3 (METTL3) as a key factor. However, the in vivo functions of METTL3 and m6A modification in mammalian development remain unclear. Here, we show that specific inactivation of Mettl3 in mouse nervous system causes severe developmental defects in the brain. Mettl3 conditional knockout (cKO) mice manifest cerebellar hypoplasia caused by drastically enhanced apoptosis of newborn cerebellar granule cells (CGCs) in the external granular layer (EGL). METTL3 depletion–induced loss of m6A modification causes extended RNA half-lives and aberrant splicing events, consequently leading to dysregulation of transcriptome-wide gene expression and premature CGC death. Our findings reveal a critical role of METTL3-mediated m6A in regulating the development of mammalian cerebellum.

Aims/hypothesis In humans, one of the hallmarks of type 2 diabetes is a reduced plasma concentration of HDL and its major protein component, apolipoprotein A

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.

N 6-methyladenosine (m6A) is one of the most abundant modifications on mRNAs and plays important roles in various biological processes. The formation of m6A is catalyzed by a methyltransferase complex (MTC) containing a key factor methyltransferase-like 3 (Mettl3). However, the functions of Mettl3 and m6A modification in hepatic lipid and glucose metabolism remain unclear. Here, we showed that both Mettl3 expression and m6A level increased in the livers of mice with high fat diet (HFD)-induced metabolic disorders. Overexpression of Mettl3 aggravated HFD-induced liver metabolic disorders and insulin resistance. In contrast, hepatocyte-specific knockout of Mettl3 significantly alleviated HFD-induced metabolic disorders by slowing weight gain, reducing lipid accumulation, and improving insulin sensitivity. Mechanistically, Mettl3 depletion-mediated m6A loss caused extended RNA half-lives of metabolism-related genes, which consequently protected mice against HFD-induced metabolic syndrome. Our findings reveal a critical role of Mettl3-mediated m6A in HFD-induced metabolic disorders and hepatogenous diabetes.

No abstract

Whole-body regeneration of planarians is a natural wonder but how it occurs remains elusive. It requires coordinated responses from each cell in the remaining tissue with spatial awareness to regenerate new cells and missing body parts. While previous studies identified new genes essential to regeneration, a more efficient screening approach that can identify regeneration-associated genes in the spatial context is needed. Here, we present a comprehensive three-dimensional spatiotemporal transcriptomic landscape of planarian regeneration. We describe a pluripotent neoblast subtype, and show that depletion of its marker gene makes planarians more susceptible to sub-lethal radiation. Furthermore, we identified spatial gene expression modules essential for tissue development. Functional analysis of hub genes in spatial modules, such as plk1, shows their important roles in regeneration. Our three-dimensional transcriptomic atlas provides a powerful tool for deciphering regeneration and identifying homeostasis-related genes, and provides a publicly available online spatiotemporal analysis resource for planarian regeneration research.

Background: Planarian has attracted increasing attentions in the regeneration field for its usefulness as an important biological model organism attributing to its strong regeneration ability. Both the complexity of multiple regulatory networks and their coordinate functions contribute to the maintenance of normal cellular homeostasis and the process of regeneration in planarian. The polarity, size, location and number of regeneration tissues are regulated by diverse mechanisms. In this review we summarize the recent advances about the importance genetic and molecular mechanisms for regeneration control on various tissues in planarian. Methods: A comprehensive literature search of original articles published in recent years was performed in regards to the molecular mechanism of each cell types during the planarian regeneration, including neoblast, nerve system, eye spot, excretory system and epidermal. Results: Available molecular mechanisms gave us an overview of regeneration process in every tissue. The sense of injuries and initiation of regeneration is regulated by diverse genes like follistatin and ERK signaling. The Neoblasts differentiate into tissue progenitors under the regulation of genes such as egfr-3. The regeneration polarity is controlled by Wnt pathway, BMP pathway and bioelectric signals. The neoblast within the blastema differentiate into desired cell types and regenerate the missing tissues. Those tissue specific genes regulate the tissue progenitor cells to differentiate into desired cell types to complete the regeneration process. Conclusion: All tissue types in planarian participate in the regeneration process regulated by distinct molecular factors and cellular signaling pathways. The neoblasts play vital roles in tissue regeneration and morphology maintenance. These studies provide new insights into the molecular mechanisms for regulating planarian regeneration.