Determining sequence signals for HSV-1-induced read-through transcription

• Applicant: Professorin Dr. Caroline Friedel
• Subject Area: Bioinformatics and Theoretical Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 556949204

Herpes simplex virus 1 (HSV-1) infection induces a widespread disruption of transcription termination for host genes. This leads to read-through transcription beyond polyadenylation (pA) sites for tens of thousands of nucleotides. Although most host genes are affected, the degree to which they are affected varies substantially. Furthermore, while the HSV-1 protein ICP27 is capable of inducing read-through transcription on its own, read-through is also observed in ICP27-null mutant infection. In this project, we aim to address key questions regarding HSV-1-induced read-through that remain unresolved so far: (1) For which pA sites is HSV-1-induced read-through dependent or independent of ICP27? (2) Which sequence signals determine whether a pA site is susceptible or resilient to HSV-1-induced read-through in the presence or absence of ICP27? (3) How are read-through and corresponding sequence signals linked to alternative polyadenylation and different 3’UTR lengths in different tissues? (4) How frequently are read-through transcripts polyadenylated downstream of the last "normal" pA site of a gene and does this reflect the presence or absence of pA signals in intergenic regions? To resolve these questions, we will analyze precise sequencing data of pA sites and employ cutting-edge artificial intelligence (AI) methods for predicting and scoring pA sites and binding of RNA binding proteins. For this purpose, we will leverage pre-trained deep learning models that have recently been published and apply methods for explainable AI to interpret model predictions. This will allow obtaining mechanistic insights into underlying sequence signals and design validation experiments using reporter assays performed by our collaboration partner.

• DFG Programme: Research Grants