Project description:Spatially resolved transcriptomics technologies have significantly enhanced our ability to understand cellular characteristics within tissue contexts. However, current analytical tools often treat cell type inference and cellular neighbourhood identification as separate and hard clustering processes, resulting in models that are not comparable across tissue feature scales and samples, thus hindering a unified understanding of tissue features. Our computational framework, SPARROW, addresses these challenges by representing cell types and cellular organization patterns as latent embeddings learned through an interconnected neural network architecture. SPARROW integrates clustering directly into the learning of these latent embeddings, enabling feature extraction specific to clustering while ensuring comparability across samples through shared latent spaces. When applied to diverse datasets, SPARROW outperformed state-of-the-art methods in cell type inference and microenvironment zone delineation and uncovered microenvironment zone-specific fine cell states that reveal underlying biology. Furthermore, SPARROW algorithmically achieves single cell spatial resolution and whole transcriptome coverage---an experimental challenge---by integrating spatially resolved transcriptomics and scRNA-seq data in a shared latent space. This formulation enabled SPARROW to uncover both established and novel microenvironment zone-specific ligand-receptor interactions in human tonsils---discoveries not possible with either data modality alone. Overall, SPARROW provides a comprehensive characterization of tissue features across scales, samples and conditions.
Project description:The Wnt/β-catenin signaling pathway is a critical regulator of development and stem cell maintenance. Mounting evidence suggests that the context-specific outcome of Wnt signaling is determined by the collaborative action of multiple transcription factors, including members of the highly conserved forkhead box (FOX) protein family. The contribution of FOX transcription factors to Wnt signaling has not been investigated in a systemic manner. Here, by combining β-catenin reporter assays with Wnt pathway-focused qPCR arrays and proximity proteomics of selected FOX family members, we determine that most FOX proteins are involved in the regulation of Wnt pathway activity and the expression of Wnt ligands and target genes. We conclude that FOX proteins are common regulators of the Wnt/β-catenin pathway that may control the outcome of Wnt signaling in a tissue-specific manner.
Project description:Herpes simplex virus 1 (HSV-1) switches between lytic and latent infections in neurons, yet the switch mechanisms remain obscure. Here we identify forkhead box (FOX) family proteins that can strongly activate or repress HSV-1 replication particularly in neuronal cells. Expression of activating FOX genes (Foxa, Foxc, Foxe, Foxf) is ordinarily low and expression of repressive FOX genes (Foxk) is high in neurons. Lytic HSV-1 infection and other stresses can increase activating FOX gene expression. Such overexpression or knockout of endogenous FOXK1 promotes reactivation from latency. These FOX proteins broadly associate with the viral genome and regulate viral gene transcription through epigenetic modulators. FOXF1 associates with histone acetyltransferases CBP and P300 to open viral chromatin. FOXK1 collaborates with SIN3A, a known cofactor of histone deacetylation, and MAX to suppress HSV-1 replication and antagonize activating FOX proteins. Thus, HSV-1 uses FOX family members with opposing effects to regulate the lytic-latent balance.