Yang, Z.-Q. | bioRxiv Science

bioRxiv2025

Putative long-range mossy fiber sprouting and regional hypermetabolic capacity in the hippocampus of patients with mesial temporal lobe epilepsy

Mesial temporal lobe epilepsy (MTLE) is pathologically characterized by neuronal loss in the dentate hilus, CA3 and CA1 regions, and mossy fiber (MF) sprouting into the inner molecular layer (iML). The latter forms aberrant excitatory circuities that are considered to facilitate recurrent seizures, with the subiculum also being related to epileptogenic activation. We recently identified a distinct expression of -smooth muscle actin (SMA) at the MF terminals in human hippocampus. This prompted us to explore MF sprouting in resected hippocampi (n=20) from patients with MTLE relative to postmortem control (n=20) using SMA along with reference markers for pathological cross-validation. Compared to control, neuronal loss assessed with neuron-specific nuclear antigen and sortilin immunolabeling reached CA1 in all resected hippocampi. SMA, zinc transporter 3 and {beta}-secretase 1 immunolabeling in the iML tended to be increased. The MF-related markers also revealed a preserved fibrous band extending across CA1 to subiculum. Cytochrome c oxidase immunolabeling also increased in iML and subiculum in the MTLE group. Taking together, the current findings point to the existence of long-range MF sprouting and a regional hypermetabolic compacity in the hippocampal formation of patients with drug resistant MTLE.

neuroscience↗

bioRxiv2024

Multi-omics analysis reveals CMTR1 upregulation in cancer and roles in ribosomal protein gene expression and tumor growth

The mRNA cap methyltransferase CMTR1 plays a crucial role in RNA metabolism and gene expression regulation, yet its significance in cancer remains largely unexplored. Here, we present a comprehensive multi-omics analysis of CMTR1 across various human cancers, revealing its widespread upregulation and potential as a therapeutic target. Integrating transcriptomic and proteomic data from a large set of cancer samples, we demonstrate that CMTR1 is upregulated at the mRNA, protein, and phosphoprotein levels across multiple cancer types. Functional studies using CRISPR-mediated knockout and siRNA knockdown in breast cancer models show that CMTR1 depletion significantly inhibits tumor growth both in vitro and in vivo. Transcriptomic analysis reveals that CMTR1 primarily regulates ribosomal protein genes and other transcripts containing 5 Terminal Oligopyrimidine (TOP) motifs. Additionally, CMTR1 affects the expression of snoRNA host genes and snoRNAs, suggesting a broader role in RNA metabolism. Mechanistically, we propose that CMTR1s target specificity is partly determined by mRNA structure, particularly the presence of 5TOP motifs. Furthermore, we identify a novel CMTR1 inhibitor, N97911, through in silico screening and biochemical assays, which demonstrates significant anti-tumor activity in vitro. Our findings establish CMTR1 as a key player in cancer biology, regulating critical aspects of RNA metabolism and ribosome biogenesis, and highlight its potential as a therapeutic target across multiple cancer types.

cancer biology↗