Deficiency of m A RNA methylation promotes ZBP1-mediated cell death.

m A RNA methylation suppresses the immunostimulatory potential of endogenous RNA. Deficiency of m A provokes inflammatory responses and cell death, but the underlying mechanisms remain elusive. Here we showed that the noncoding RNA 7SK gains immunostimulatory potential upon m A depletion and subsequently activates the RIG-I/MAVS axis to spark interferon (IFN) signaling cascades.

Exploring the brain epitranscriptome: perspectives from the NSAS summit.

Increasing evidence reinforces the essential function of RNA modifications in development and diseases, especially in the nervous system. RNA modifications impact various processes in the brain, including neurodevelopment, neurogenesis, neuroplasticity, learning and memory, neural regeneration, neurodegeneration, and brain tumorigenesis, leading to the emergence of a new field termed neuroepitranscriptomics. Deficiency in machineries modulating RNA modifications has been implicated in a range of brain disorders from microcephaly, intellectual disability, seizures, and psychiatric disorders to brain cancers such as glioblastoma.

Random Forest model reveals the interaction between N6-methyladenosine modifications and RNA-binding proteins.

RNA-binding proteins (RBPs) have critical roles in N6-methyladenosine (m6A) modification process. We designed a Random Forest (RF) model to systematically analyze the interaction among RBPs and m6A modifications by integrating the binding signals from hundreds of RBPs. Accurate prediction of m6A sites demonstrated significant connections between RBP bindings and m6A modifications.

Epigenetic and epitranscriptomic regulation of axon regeneration.

Effective axonal regeneration in the adult mammalian nervous system requires coordination of elevated intrinsic growth capacity and decreased responses to the inhibitory environment. Intrinsic regenerative capacity largely depends on the gene regulatory network and protein translation machinery. A failure to activate these pathways upon injury is underlying a lack of robust axon regeneration in the mature mammalian central nervous system.

METTL3 inhibition reduces N -methyladenosine levels and prevents allogeneic CD4 T-cell responses.

Alloreactive CD4 T cells play a central role in allograft rejection. However, the post-transcriptional regulation of the effector program in alloreactive CD4 T cells remains unclear. N -methyladenosine (m A) RNA modification is involved in various physiological and pathological processes.

Ablation of BATF Alleviates Transplant Rejection Abrogating the Effector Differentiation and Memory Responses of CD8 T Cells.

Allogeneic CD8 T cells are prominently involved in allograft rejection, but how their effector differentiation and function are regulated at a transcriptional level is not fully understood. Herein, we identified the basic leucine zipper ATF-like transcription factor (BATF) as a key transcription factor that drives the effector program of allogeneic CD8 T cells. We found that BATF is highly expressed in graft-infiltrating CD8 T cells, and its ablation in CD8 T cells significantly prolonged skin allograft survival in a fully MHC-mismatched transplantation model.

A contemporary review of therapeutic and regenerative management of intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) remains a common and debilitating form of stroke. This neurological emergency must be diagnosed and treated rapidly yet effectively. In this article, we review the medical, surgical, repair, and regenerative treatment options for managing ICH.

An EGFR signature predicts cell line and patient sensitivity to multiple tyrosine kinase inhibitors.

EGFR is an oncogene with a high frequency of activating mutations in nonsmall cell lung cancer (NSCLC). EGFR inhibitors have been FDA-approved for NSCLC and have shown efficacy in patients with certain EGFR mutations. However, only 9% to 26% of these patients achieve objective responses.

Knocking Out Non-muscle Myosin II in Retinal Ganglion Cells Promotes Long-Distance Optic Nerve Regeneration.

In addition to altered gene expression, pathological cytoskeletal dynamics in the axon are another key intrinsic barrier for axon regeneration in the central nervous system (CNS). Here, we show that knocking out myosin IIA and IIB (myosin IIA/B) in retinal ganglion cells alone, either before or after optic nerve crush, induces significant optic nerve regeneration. Combined Lin28a overexpression and myosin IIA/B knockout lead to an additive promoting effect and long-distance axon regeneration.

mA mRNA Methylation Is Essential for Oligodendrocyte Maturation and CNS Myelination.

The molecular mechanisms that govern the maturation of oligodendrocyte lineage cells remain unclear. Emerging studies have shown that N-methyladenosine (mA), the most common internal RNA modification of mammalian mRNA, plays a critical role in various developmental processes. Here, we demonstrate that oligodendrocyte lineage progression is accompanied by dynamic changes in mA modification on numerous transcripts.

mA facilitates hippocampus-dependent learning and memory through YTHDF1.

N-methyladenosine (mA), the most prevalent internal RNA modification on mammalian messenger RNAs, regulates the fates and functions of modified transcripts through mA-specific binding proteins. In the nervous system, mA is abundant and modulates various neural functions. Whereas mA marks groups of mRNAs for coordinated degradation in various physiological processes, the relevance of mA for mRNA translation in vivo remains largely unknown.

Epitranscriptomic mA Regulation of Axon Regeneration in the Adult Mammalian Nervous System.

N-methyladenosine (mA) affects multiple aspects of mRNA metabolism and regulates developmental transitions by promoting mRNA decay. Little is known about the role of mA in the adult mammalian nervous system. Here we report that sciatic nerve lesion elevates levels of mA-tagged transcripts encoding many regeneration-associated genes and protein translation machinery components in the adult mouse dorsal root ganglion (DRG).

An Intrinsic Epigenetic Barrier for Functional Axon Regeneration.

Mature neurons in the adult peripheral nervous system can effectively switch from a dormant state with little axonal growth to robust axon regeneration upon injury. The mechanisms by which injury unlocks mature neurons' intrinsic axonal growth competence are not well understood. Here, we show that peripheral sciatic nerve lesion in adult mice leads to elevated levels of Tet3 and 5-hydroxylmethylcytosine in dorsal root ganglion (DRG) neurons.

Epigenetic regulation of axonal regenerative capacity.

The intrinsic growth capacity of neurons in the CNS declines during neuronal maturation, while neurons in the adult PNS are capable of regeneration. Injured mature PNS neurons require activation of an array of regeneration-associated genes to regain axonal growth competence. Accumulating evidence indicates a pivotal role of epigenetic mechanisms in transcriptional reprogramming and regulation of neuronal growth ability upon injury.

Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair.

Contrary to the long-held belief that DNA methylation of terminally differentiated cells is permanent and essentially immutable, post-mitotic neurons exhibit extensive DNA demethylation. The cellular function of active DNA demethylation in neurons, however, remains largely unknown. Tet family proteins oxidize 5-methylcytosine to initiate active DNA demethylation through the base-excision repair (BER) pathway.

Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury.

Contusive spinal cord injury leads to a variety of disabilities owing to limited neuronal regeneration and functional plasticity. It is well established that an upregulation of glial-derived chondroitin sulphate proteoglycans (CSPGs) within the glial scar and perineuronal net creates a barrier to axonal regrowth and sprouting. Protein tyrosine phosphatase σ (PTPσ), along with its sister phosphatase leukocyte common antigen-related (LAR) and the nogo receptors 1 and 3 (NgR), have recently been identified as receptors for the inhibitory glycosylated side chains of CSPGs.

DNA modifications and neurological disorders.

Mounting evidence has recently underscored the importance of DNA methylation in normal brain functions. DNA methylation machineries are responsible for dynamic regulation of methylation patterns in discrete brain regions. In addition to methylation of cytosines in genomic DNA (5-methylcytosine; 5mC), other forms of modified cytosines, such as 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine, can potentially act as epigenetic marks that regulate gene expression.

The cytoplasmic adaptor protein Caskin mediates Lar signal transduction during Drosophila motor axon guidance.

The multiprotein complexes that receive and transmit axon pathfinding cues during development are essential to circuit generation. Here, we identify and characterize the Drosophila sterile α-motif (SAM) domain-containing protein Caskin, which shares homology with vertebrate Caskin, a CASK [calcium/calmodulin-(CaM)-activated serine-threonine kinase]-interacting protein. Drosophila caskin (ckn) is necessary for embryonic motor axon pathfinding and interacts genetically and physically with the leukocyte common antigen-related (Lar) receptor protein tyrosine phosphatase.

Costars, a Dictyostelium protein similar to the C-terminal domain of STARS, regulates the actin cytoskeleton and motility.

Through analysis of a chemotaxis mutant obtained from a genetic screen in Dictyostelium discoideum, we have identified a new gene involved in regulating cell migration and have named it costars (cosA). The 82 amino acid Costars protein sequence appears highly conserved among diverse species, and significantly resembles the C-terminal region of the striated muscle activator of Rho signaling (STARS), a mammalian protein that regulates the serum response factor transcriptional activity through actin binding and Rho GTPase activation. The cosA-null (cosA(-)) cells formed smooth plaques on bacterial lawns, produced abnormally small fruiting bodies when developed on the non-nutrient agar and displayed reduced migration towards the cAMP source in chemotactic assays.

Dictyostelium gnt15 encodes a protein with similarity to LARGE and plays an essential role in development.

LARGE is a putative glycosyltransferase found to be mutated in mice with myodystrophy or patients with congenital muscular dystrophy. By homology searches, we identified in the Dictyostelium discoideum genome four open reading frames, i.e.