Biology subjects

Soelter, T. M.

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

5 recordsLinked to original sources

bioRxiv2024

Cell-type-specific alternative splicing in the cerebral cortex of a Schinzel-Giedion Syndrome patient variant mouse model

Schinzel-Giedion Syndrome (SGS) is an ultra-rare Mendelian disorder caused by gain-of-function mutations in the SETBP1 gene. While previous studies determined multiple roles for how SETBP1 and associated pathways may cause disease manifestation, they have not assessed whether cell-type-specific alternative splicing (AS) plays a role in SGS. We quantified gene and splice junction (SJ) expression from snRNA-seq data we previously generated from the cerebral cortex and the kidney of an atypical Setbp1S858R SGS patient variant (n = 3) and wild-type (n = 3) mice. We performed pseudobulk differential gene expression and SJ usage (SJU) analyses across cell types and conditions. We identified 33 and 62 genes with statistically significant alterations in SJU in the brain and the kidney, respectively. Astrocytes and T cells had the most genes with cell-type-specific changes in SJU (n = 6 each) in the brain and kidney, respectively. We identified significant SJU in a member of the heterogeneous nuclear ribonucleoprotein family, Hnrnpa2b1. These findings were cell-type-specific for inhibitory neurons in the cerebral cortex and cell-type-agnostic in the kidney, suggesting tissue-specificity of AS in Setbp1S858R mice. To broaden the impact of our results for the rare disease community, we developed a point-and-click web application as a resource for users to explore single-cell resolution changes in the presence of Setbp1S858R at the gene and splice junction level. Overall, we find that AS may be implicated in a tissue- and cell-type-specific manner in the cerebral cortex and kidney of Setbp1S858R mice.

genomics↗

bioRxiv2024

Evaluation of altered cell-cell communication between glia and neurons in the hippocampus of 3xTg-AD mice at two time points

Alzheimers disease (AD) is the most common form of dementia and is characterized by progressive memory loss and cognitive decline, affecting behavior, speech, and motor abilities. The neuropathology of AD includes the formation of extracellular amyloid-{beta} plaque and intracellular neurofibrillary tangles of phosphorylated tau, along with neuronal loss. While neuronal loss is an AD hallmark, cell-cell communication between neuronal and non-neuronal cell populations maintains neuronal health and brain homeostasis. To study changes in cellcell communication during disease progression, we performed snRNA-sequencing of the hippocampus from female 3xTg-AD and wild-type littermates at 6 and 12 months. We inferred differential cell-cell communication between 3xTg-AD and wild-type mice across time points and between senders (astrocytes, microglia, oligodendrocytes, and OPCs) and receivers (excitatory and inhibitory neurons) of interest. We also assessed the downstream effects of altered glia-neuron communication using pseudobulk differential gene expression, functional enrichment, and gene regulatory analyses. We found that glia-neuron communication is increasingly dysregulated in 12-month 3xTg-AD mice. We also identified 23 AD-associated ligand-receptor pairs that are upregulated in the 12-month-old 3xTg-AD hippocampus. Our results suggest increased AD association of interactions originating from microglia. Signaling mediators were not significantly differentially expressed but showed altered gene regulation and TF activity. Our findings indicate that altered glia-neuron communication is increasingly dysregulated and affects the gene regulatory mechanisms in neurons of 12-month-old 3xTg-AD mice.

genomics↗

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↗