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Glioblastoma (GBM) is the most common type of adult malignant brain tumor, but its molecular mechanisms are not well understood. In addition, the knowledge of the disease-associated expression and function of YTHDF2 remains very limited. Here, we show that YTHDF2 overexpression clinically correlates with poor glioma patient prognosis. EGFR that is constitutively activated in the majority of GBM causes YTHDF2 overexpression through the EGFR/SRC/ERK pathway. EGFR/SRC/ERK signaling phosphorylates YTHDF2 serine39 and threonine381, thereby stabilizes YTHDF2 protein. YTHDF2 is required for GBM cell proliferation, invasion, and tumorigenesis. YTHDF2 facilitates m 6 A-dependent mRNA decay of LXRA and HIVEP2 , which impacts the glioma patient survival. YTHDF2 promotes tumorigenesis of GBM cells, largely through the downregulation of LXRα and HIVEP2. Furthermore, YTHDF2 inhibits LXRα-dependent cholesterol homeostasis in GBM cells. Together, our findings extend the landscape of EGFR downstream circuit, uncover the function of YTHDF2 in GBM tumorigenesis, and highlight an essential role of RNA m 6 A methylation in cholesterol homeostasis. EGFR is frequently constitutively active in glioblastoma (GBM). Here, the authors show that EGFR induces YTHDF2 protein stabilization, which reduces cholesterol homeostasis through an RNA m6A methylation dependent molecular mechanism to promote GBM tumourigenesis.

Quantifying RNAs in their spatial context is crucial to understanding gene expression and regulation in complex tissues. In situ transcriptomic methods generate spatially resolved RNA profiles in intact tissues. However, there is a lack of a unified computational framework for integrative analysis of in situ transcriptomic data. Here, we introduce an unsupervised and annotation-free framework, termed ClusterMap, which incorporates the physical location and gene identity of RNAs, formulates the task as a point pattern analysis problem, and identifies biologically meaningful structures by density peak clustering (DPC). Specifically, ClusterMap precisely clusters RNAs into subcellular structures, cell bodies, and tissue regions in both two- and three-dimensional space, and performs consistently on diverse tissue types, including mouse brain, placenta, gut, and human cardiac organoids. We demonstrate ClusterMap to be broadly applicable to various in situ transcriptomic measurements to uncover gene expression patterns, cell niche, and tissue organization principles from images with high-dimensional transcriptomic profiles. In situ transcriptomics maps RNA expression patterns across intact tissues taking our understanding of gene expression to a new level. Here, the authors present a computational method that uncovers gene expression, cell niche, and tissue region patterns from 2D and 3D spatial transcriptomics.

RNA contains over 150 types of chemical modifications. Although many of these chemical modifications were discovered several decades ago, their functions were not immediately apparent. Discoveries of RNA demethylases, along with advances in mass spectrometry and high-throughput sequencing techniques, have caused research into RNA modifications to progress at an accelerated rate. Post-transcriptional RNA modifications make up an epitranscriptome that extensively regulates gene expression and biological processes. Here, we present an overview of recent advances in the field that are shaping our understanding of chemical modifications, their impact on development and disease, and the dynamic mechanisms through which they regulate gene expression.

Background N 6 -methyladenosine (m 6 A) modification in mRNAs was recently shown to be dynamically regulated, indicating a pivotal role in multiple developmental processes. Most recently, it was shown that the Mettl3-Mettl14 writer complex of this mark is required for the temporal control of cortical neurogenesis. The m 6 A reader protein Ythdf2 promotes mRNA degradation by recognizing m 6 A and recruiting the mRNA decay machinery. Results We show that the conditional depletion of the m 6 A reader protein Ythdf2 in mice causes lethality at late embryonic developmental stages, with embryos characterized by compromised neural development. We demonstrate that neural stem/progenitor cell (NSPC) self-renewal and spatiotemporal generation of neurons and other cell types are severely impacted by the loss of Ythdf2 in embryonic neocortex. Combining in vivo and in vitro assays, we show that the proliferation and differentiation capabilities of NSPCs decrease significantly in Ythdf2 −/− embryos. The Ythdf2 −/− neurons are unable to produce normally functioning neurites, leading to failure in recovery upon reactive oxygen species stimulation. Consistently, expression of genes enriched in neural development pathways is significantly disturbed. Detailed analysis of the m 6 A-methylomes of Ythdf2 −/− NSPCs identifies that the JAK-STAT cascade inhibitory genes contribute to neuroprotection and neurite outgrowths show increased expression and m 6 A enrichment. In agreement with the function of Ythdf2, delayed degradation of neuron differentiation-related m 6 A-containing mRNAs is seen in Ythdf2 −/− NSPCs. Conclusions We show that the m 6 A reader protein Ythdf2 modulates neural development by promoting m 6 A-dependent degradation of neural development-related mRNA targets.

Spatially charting molecular cell types at single-cell resolution across the 3D volume is critical for illustrating the molecular basis of brain anatomy and functions. Single-cell RNA sequencing has profiled molecular cell types in the mouse brain 1 , 2 , but cannot capture their spatial organization. Here we used an in situ sequencing method, STARmap PLUS 3 , 4 , to profile 1,022 genes in 3D at a voxel size of 194 × 194 × 345 nm 3 , mapping 1.09 million high-quality cells across the adult mouse brain and spinal cord. We developed computational pipelines to segment, cluster and annotate 230 molecular cell types by single-cell gene expression and 106 molecular tissue regions by spatial niche gene expression. Joint analysis of molecular cell types and molecular tissue regions enabled a systematic molecular spatial cell-type nomenclature and identification of tissue architectures that were undefined in established brain anatomy. To create a transcriptome-wide spatial atlas, we integrated STARmap PLUS measurements with a published single-cell RNA-sequencing atlas 1 , imputing single-cell expression profiles of 11,844 genes. Finally, we delineated viral tropisms of a brain-wide transgene delivery tool, AAV-PHP.eB 5 , 6 . Together, this annotated dataset provides a single-cell resource that integrates the molecular spatial atlas, brain anatomy and the accessibility to genetic manipulation of the mammalian central nervous system. In situ spatial transcriptomic analysis of more than 1 million cells are used to create a 200-nm-resolution spatial molecular atlas of the adult mouse central nervous system and identify previously unknown tissue architectures.

N 6 -methyladenosine (m 6 A), the most prevalent internal RNA modification on mammalian messenger RNAs, regulates the fates and functions of modified transcripts through m 6 A-specific binding proteins 1 – 5 . In the nervous system, m 6 A is abundant and modulates various neural functions 6 – 11 . Whereas m 6 A marks groups of mRNAs for coordinated degradation in various physiological processes 12 – 15 , the relevance of m 6 A for mRNA translation in vivo remains largely unknown. Here we show that, through its binding protein YTHDF1, m 6 A promotes protein translation of target transcripts in response to neuronal stimuli in the adult mouse hippocampus, thereby facilitating learning and memory. Mice with genetic deletion of Ythdf1 show learning and memory defects as well as impaired hippocampal synaptic transmission and long-term potentiation. Re-expression of YTHDF1 in the hippocampus of adult Ythdf1 -knockout mice rescues the behavioural and synaptic defects, whereas hippocampus-specific acute knockdown of Ythdf1 or Mettl3 , which encodes the catalytic component of the m 6 A methyltransferase complex, recapitulates the hippocampal deficiency. Transcriptome-wide mapping of YTHDF1-binding sites and m 6 A sites on hippocampal mRNAs identified key neuronal genes. Nascent protein labelling and tether reporter assays in hippocampal neurons showed that YTHDF1 enhances protein synthesis in a neuronal-stimulus-dependent manner. In summary, YTHDF1 facilitates translation of m 6 A-methylated neuronal mRNAs in response to neuronal stimulation, and this process contributes to learning and memory. Neuronal stimulation induces protein translation of m 6 A-methylated neuronal mRNAs facilitated by YTHDF1, and this process contributes to learning and memory.

As one of the most critical components in lithium-ion batteries (LIBs), commercial polyolefin separators suffer from drawbacks such as poor thermal stability and the inability to inhibit the growth of dendrites, which seriously threaten the safety of LIBs. In this study, we prepared calcium alginate fiber/boron nitride-compliant separators (CA@BN) through paper-making technology and the surface coating method using calcium alginate fiber and boron nitride. The CA@BN had favorable electrolyte wettability, flame retardancy, and thermal dimensional stability of the biomass fiber separator. Meanwhile, the boron nitride coating provided excellent thermal conductivity and mechanical strength for the composite separator, which inhibited the growth of lithium dendrites and enabled lithium-ion symmetric batteries to achieve more than 1000 stable and long cycles at a current density of 0.5 mA cm−2. The interwoven fiber mesh formed by the boron nitride coating and the calcium alginate provided multiple pathways for ion migration, which enhanced the storage capacity of the electrolyte, improved the interfacial compatibility between the separator and the electrode, widened the window of electrochemical stability, and enhanced ionic migration. This eco-friendly bio-based separator paves a new insight for the design of heat-resistance separators as well as the safe running of LIBs.

N6-methyladenosine （m6A） is the most abundant internal modification in eukaryotic messenger RNAs （mRNAs）, and plays important roles in cell differentiation and tissue development. It regulates multiple steps throughout the RNA life cycle including RNA processing, translation, and decay, via the recognition by selective binding proteins. In the cytoplasm, m~A binding protein YTHDF1 facilitates translation of m6A-modified mRNAs, and YTHDF2 acceler- ates the decay of m6A-modified transcripts. The biological function of YTHDF3, another cytoplasmic m6A binder of the YTH （YT521-B homology） domain family, remains unknown. Here, we report that YTHDF3 promotes protein synthesis in synergy with YTHDFI, and affects methylated mRNA decay mediated through YTHDF2. Cells defcient in all three YTHDF proteins experience the most dramatic accumulation of m6A-modified transcripts. These results indicate that together with YTHDF1 and YTHDF2, YTHDF3 plays critical roles to accelerate metabolism of m6A-modified mRNAs in the cytoplasm. All three YTHDF proteins may act in an integrated and cooperative manner to impact fundamental biological processes related to m6A RNA methylation.

N 6 -methyladenosine (m 6 A) is the most prevalent modification in eukaryotic messenger RNAs (mRNAs) and is interpreted by its readers, such as YTH domain-containing proteins, to regulate mRNA fate. Here, we report the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs; including IGF2BP1/2/3) as a distinct family of m 6 A readers that target thousands of mRNA transcripts through recognizing the consensus GG(m 6 A)C sequence. In contrast to the mRNA-decay-promoting function of YTH domain-containing family protein 2, IGF2BPs promote the stability and storage of their target mRNAs (for example, MYC ) in an m 6 A-dependent manner under normal and stress conditions and therefore affect gene expression output. Moreover, the K homology domains of IGF2BPs are required for their recognition of m 6 A and are critical for their oncogenic functions. Thus, our work reveals a different facet of the m 6 A-reading process that promotes mRNA stability and translation, and highlights the functional importance of IGF2BPs as m 6 A readers in post-transcriptional gene regulation and cancer biology. Huang et al. identify IGF2BPs as an additional class of N 6 -methyladenosine (m 6 A) reader proteins. They find that IGF2BPs selectively bind to m 6 A-containing mRNAs and promote their stability.

N^6-methyladenosine （m^6A） is the most common internal modification in eukaryotic mRNA. It is dynamically in- stalled and removed, and acts as a new layer of mRNA metabolism, regulating biological processes including stem cell pluripotency, cell differentiation, and energy homeostasis, m^6A is recognized by selective binding proteins; YTHDF1 and YTHDF3 work in concert to affect the translation of m^6A-containing mRNAs, YTHDF2 expedites mRNA decay, and YTHDC1 affects the nuclear processing of its targets. The biological function of YTHDC2, the final member of the YTH protein family, remains unknown. We report that YTHDC2 selectively binds m6A at its consensus motif. YTHDC2 enhances the translation efficiency of its targets and also decreases their mRNA abundance. Ythdc2 knock- out mice are infertile; males have significantly smaller testes and females have significantly smaller ovaries compared to those oflittermates. The germ cells of Ythdc2 knockout mice do not develop past the zygotene stage and according- ly, Ythdc2 is upregulated in the testes as meiosis begins. Thus, YTHDC2 is an m6A-binding protein that plays critical roles during svermatogenesis.