Biology subjects

Soelter, T. M.

Publications and source records attributed to Soelter, T. M..

3 recordsLinked to original sources

bioRxiv2023

Altered Glia-Neuron Communication in Alzheimer's Disease Affects WNT, p53, and NFkB Signaling Determined by snRNA-seq

BackgroundAlzheimers disease is the most common cause of dementia and is characterized by amyloid-{beta} plaques, tau neurofibrillary tangles, and neuronal loss. Although neuronal loss is a primary hallmark of Alzheimers disease, it is known that non-neuronal cell populations are ultimately responsible for maintaining brain homeostasis and neuronal health through neuron-glia and glial cell crosstalk. Many signaling pathways have been proposed to be dysregulated in Alzheimers disease, including WNT, TGF{beta}, p53, mTOR, NFkB, and Pi3k/Akt signaling. Here, we predict altered cell-cell communication between glia and neurons. MethodsUsing public snRNA-sequencing data generated from postmortem human prefrontal cortex, we predicted altered cell-cell communication between glia (astrocytes, microglia, oligodendrocytes, and oligodendrocyte progenitor cells) and neurons (excitatory and inhibitory). We confirmed interactions in a second and third independent orthogonal dataset. We determined cell-type-specificity using Jaccard Similarity Index and investigated the downstream effects of altered interactions in inhibitory neurons through gene expression and transcription factor activity analyses of signaling mediators. Finally, we determined changes in pathway activity in inhibitory neurons. ResultsCell-cell communication between glia and neurons is altered in Alzheimers disease in a cell-type-specific manner. As expected, ligands are more cell-type-specific than receptors and targets. We identified ligand-receptor pairs in three independent datasets and found involvement of the Alzheimers disease risk genes APP and APOE across datasets. Most of the signaling mediators of these interactions were not differentially expressed, however, the mediators that are also transcription factors had differential activity between AD and control. Namely, MYC and TP53, which are associated with WNT and p53 signaling, respectively, had decreased TF activity in Alzheimers disease, along with decreased WNT and p53 pathway activity in inhibitory neurons. Additionally, inhibitory neurons had both increased NFkB signaling pathway activity and increased TF activity of NFIL3, an NFkB signaling-associated transcription factor. ConclusionsCell-cell communication between glia and neurons in Alzheimers disease is altered in a cell-type-specific manner involving Alzheimers disease risk genes. Signaling mediators had altered transcription factor activity suggesting altered glia-neuron interactions may dysregulate signaling pathways including WNT, p53, and NFkB in inhibitory neurons.

genomics↗

bioRxiv2023

Cell-type-specific gene expression and regulation in the cerebral cortex and kidney of atypical Setbp1S858R Schinzel Giedion Syndrome mice

Schinzel Giedion Syndrome (SGS) is an ultra-rare autosomal dominant Mendelian disease presenting with abnormalities spanning multiple organ systems. The most notable phenotypes involve severe developmental delay, progressive brain atrophy, and drug-resistant seizures. SGS is caused by spontaneous variants in SETBP1, which encodes for the epigenetic hub SETBP1 transcription factor (TF). SETBP1 variants causing classical SGS cluster at the degron, disrupting SETBP1 protein degradation resulting in toxic accumulation, while those located outside cause milder atypical SGS. Due to the multi-system phenotype, we evaluated gene expression and regulatory programs altered in atypical SGS by snRNA-seq of cerebral cortex and kidney of Setbp1S858R heterozygous mice (corresponds to the human likely pathogenic SETBP1S867R variant) compared to matched wild-type mice by constructing cell-type-specific regulatory networks. Setbp1 was differentially expressed in excitatory neurons, but known SETBP1 targets were differentially expressed and regulated in many cell types. Our findings suggest molecular drivers underlying neurodevelopmental phenotypes in classical SGS also drive atypical SGS, persist after birth, and are present in the kidney. Our results indicate SETBP1s role as an epigenetic hub leads to cell-type-specific differences in TF activity, gene targeting, and regulatory rewiring. This research provides a framework for investigating cell-type-specific variant impact on gene expression and regulation.

genomics↗

bioRxiv2023

Inferring chromosomal instability from copy number aberrations as a measure of chromosomal instability across human cancers

BackgroundCancer is a complex disease that is the second leading cause of death in the United States. Despite research efforts, the ability to manage cancer and select optimal therapeutic responses for each patient remains elusive. Chromosomal instability (CIN) is primarily a product of segregation errors wherein one or many chromosomes, in part or whole, vary in number. CIN is an enabling characteristic of cancer, contributes to tumor-cell heterogeneity, and plays a crucial role in the multistep tumorigenesis process, especially in tumor growth and initiation and in response to treatment. AimsMultiple studies have reported different metrics for analyzing copy number aberrations as surrogates of CIN from DNA copy number variation data. However, these metrics differ in how they are calculated with respect to the type of variation, the magnitude of change, and the inclusion of breakpoints. Here we compared metrics capturing CIN as either numerical aberrations, structural aberrations, or a combination of the two across 33 cancer data sets from The Cancer Genome Atlas (TCGA). Methods and resultsUsing CIN inferred by methods in the CINmetrics R package, we evaluated how six copy number CIN surrogates compared across TCGA cohorts by assessing each across tumor types, as well as how they associate with tumor stage, metastasis, and nodal involvement, and with respect to patient sex. ConclusionsWe found that the tumor type impacts how well any two given CIN metrics correlate. While we also identified overlap between metrics regarding their association with clinical characteristics and patient sex, there was not complete agreement between metrics. We identified several cases where only one CIN metric was significantly associated with a clinical characteristic or patient sex for a given tumor type. Therefore, caution should be used when describing CIN based on a given metric or comparing it to other studies.

genomics↗