Jonas, C. | bioRxiv Science

bioRxiv2024

Single cell analysis of Barrett's esophagus and carcinoma reveals cell types conferring risk via genetic predisposition

Inherited genetic variants contribute to Barretts esophagus (BE) and esophageal adenocarcinoma (EAC) but it is unknown which cell types are involved in this process. We performed single cell RNA-sequencing of BE, EAC and paired normal tissues and integrated data of a genome-wide association study to determine cell type-specific genetic risk and cellular processes that contribute to BE and EAC. The analysis revealed that EAC development is driven to a greater extent by local cellular processes than BE development. One cell type of BE origin (BE-EAC) and cellular processes that control the differentiation of columnar cells are of particular relevance for EAC development. Further, specific subtypes of fibroblasts and endothelial cells contribute to BE and EAC development, while dendritic cells and CD4+ memory T cells contribute exclusively to BE development. The diagnostic use of markers characterizing the identified cell types and cellular processes should be explored in future for EAC prediction.

cancer biology↗

bioRxiv2019

An epitranscriptomic switch at the 5′-UTR controls genome selection during HIV-1 genomic RNA packaging

During retroviral replication, the full-length RNA serves both as mRNA and genomic RNA (gRNA). While the simple retrovirus MLV segregates its full-length RNA into two functional populations, the HIV-1 full-length RNA was proposed to exist as a single population used indistinctly for protein synthesis or packaging. However, the mechanisms by which the HIV-1 Gag protein selects the two RNA molecules that will be packaged into nascent virions remain poorly understood. Here, we demonstrate that HIV-1 full-length RNA packaging is regulated through an epitranscriptomic switch requiring demethylation of two conserved adenosine residues present within the 5'-UTR. As such, while m6A deposition by METTL3/METTL14 onto the full-length RNA was associated with increased Gag synthesis and reduced packaging, FTO-mediated demethylation was required for the incorporation of the full-length RNA into viral particles. Interestingly, HIV-1 Gag associates with the RNA demethylase FTO in the nucleus and drives full-length RNA demethylation. Finally, the specific inhibition of the FTO RNA demethylase activity suppressed HIV-1 full-length RNA packaging. Together, our data propose a novel epitranscriptomic mechanism allowing the selection of the full-length RNA molecules that will be used as viral genomes.

molecular biology↗