Biology subjects

Schreiner, S.

Publications and source records attributed to Schreiner, S..

3 recordsLinked to original sources

bioRxiv2024

Merkel cell polyomavirus small tumor antigen contributes to immune evasion by interfering with type I interferon signaling

Merkel cell polyomavirus (MCPyV) is the causative agent of the majority of Merkel cell carcinomas (MCC). The virus has limited coding capacity, with its early viral proteins, large T (LT) and small T (sT), being multifunctional and contributing to infection and transformation. A fundamental difference in early viral gene expression between infection and MCPyV-driven tumorigenesis is the expression of a truncated LT (LTtr) in the tumor. In contrast, sT is expressed in both conditions and contributes significantly to oncogenesis. Here, we identified novel functions of early viral proteins by performing genome-wide transcriptome and chromatin studies in primary human fibroblasts. Due to current limitations in infection and tumorigenesis models, we mimic these conditions by ectopically expressing sT, LT or LTtr, individually or in combination, at different time points. In addition to its known function in cell cycle and inflammation modulation, we reveal a fundamentally new function of sT. We show that sT regulates the type I interferon (IFN) response downstream of the type I interferon receptor (IFNAR) by interfering with the interferon-stimulated gene factor 3 (ISGF3)-induced interferon-stimulated gene (ISG) response. Expression of sT leads to a reduction in the expression of interferon regulatory factor 9 (IRF9) which is a central component of the ISGF3 complex. We further show that this function of sT is conserved in BKPyV. We provide a first mechanistic understanding of which early viral proteins trigger and control the type I IFN response, which may influence MCPyV infection, persistence and, during MCC progression, regulation of the tumor microenvironment. Author SummaryMerkel cell polyomavirus (MCPyV) is the only human polyomavirus that causes cancer in humans. As with all human polyomaviruses, the available infection models are limited. Thus, many processes such as the host response to infection and its regulation by the virus to establish infection and persistence are poorly understood. To better understand this interplay of viral MCPyV proteins, we performed genome-wide transcriptome and chromatin studies in primary human fibroblasts and simulated infection and tumorigenesis conditions by ectopically expressing the early viral proteins individually or in combination at different time points. This allowed us to uncover a novel, previously undescribed function of polyomavirus sT, namely the reduction of the ISG response by affecting the ISGF3 complex, specifically by reducing IRF9 protein levels. This work sheds light on how early viral proteins influence the type I IFN response and how their interplay may affect MCPyV infection, persistence, and MCC progression.

molecular biology↗

bioRxiv2024

Nanopore Guided Annotation of Transcriptome Architectures

High-resolution annotations of transcriptomes from all domains of life are essential for many sequencing-based RNA analyses, including Nanopore direct RNA sequencing (DRS), which would otherwise be hindered by misalignments and other analysis artefacts. DRS allows the capture and full-length sequencing of native RNAs, without recoding or amplification bias, and resulting data may be interrogated to define the identity and location of chemically modified ribonucleotides, as well as the length of poly(A) tails on individual RNA molecules. Existing software solutions for generating high-resolution transcriptome annotations are poorly suited to small gene dense organisms such as viruses due to the challenge of identifying distinct transcript isoforms where alternative splicing and overlapping RNAs are prevalent. To resolve this, we identified key characteristics of DRS datasets and developed a novel approach to transcriptome. We demonstrate, using a combination of synthetic and original datasets, that our novel approach yields a high level of precision and recall when reconstructing both gene sparse and gene dense transcriptomes from DRS datasets. We further apply this approach to generate a new high resolution transcriptome annotation of the neglected pathogen human adenovirus type F 41 for which we identify 77 distinct transcripts encoding at least 23 different proteins.

bioinformatics↗

bioRxiv2024

DEAD-box ATPase Dbp2 mediates mRNA release after 3'-end formation

mRNA biogenesis in the eukaryotic nucleus is a highly complex process. The numerous RNA processing steps are tightly coordinated to ensure that only fully processed transcripts are released from chromatin for export from the nucleus. Here, we present the hypothesis that fission yeast Dbp2, a ribonucleoprotein complex (RNP) remodelling ATPase of the DEAD-box family, is the key enzyme in an RNP assembly checkpoint at the 3-end of genes. We show that Dbp2 interacts with the cleavage and polyadenylation complex (CPAC) and localizes to cleavage bodies, which are enriched for 3-end processing factors and proteins involved in nuclear RNA surveillance. Upon loss of Dbp2, 3-processed, polyadenylated RNAs accumulate on chromatin and in cleavage bodies, and CPAC components are depleted from the soluble pool. Under these conditions, cells display an increased likelihood to skip polyadenylation sites and a delayed transcription termination, suggesting that levels of free CPAC components are insufficient to maintain normal levels of 3-end processing. Our data support a model in which Dbp2 is the active component of an mRNP remodelling checkpoint that licenses RNA export and is coupled to CPAC release.

molecular biology↗