Biology subjects

Labadorf, A. T.

Publications and source records attributed to Labadorf, A. T..

4 recordsLinked to original sources

bioRxiv2023

Heterogeneity of novel APOER2 isoforms specific to Alzheimer disease impact cellular and synaptic states

Apolipoprotein receptor 2 (APOER2) is an alternatively spliced transmembrane receptor that binds the neuroprotective ligand Reelin and Alzheimers disease (AD) related risk factor, APOE. Splicing of single exons in mouse Apoer2 regulates neuronal function and synaptic plasticity. However, the splicing landscape and function of human APOER2 isoforms in physiological and AD conditions remains unclear. Here, we identified over 200 unique human APOER2 isoforms in the parietal cortex and hippocampus with 151 isoforms common between the two brain regions. In addition, we identified region- and AD-specific APOER2 isoforms suggesting APOER2 splicing is spatially regulated and altered in AD. We tested whether the AD-specific APOER2 transcripts have distinct functional properties, and demonstrated AD-specific APOER2 variants have altered cell surface expression, APOE-mediated receptor processing and synaptic changes which could contribute to neuronal dysfunction associated with AD pathogenesis.

neuroscience↗

bioRxiv2022

Widespread perturbation of ETS factor binding sites in cancer

Although >90% of somatic mutations reside in non-coding regions, few have been reported as cancer drivers. To predict driver non-coding variants (NCVs), we present a novel transcription factor (TF)-aware burden test (TFA-BT) based on a model of coherent TF function in promoters. We applied our TFA-BT to NCVs from the Pan-Cancer Analysis of Whole Genomes cohort and predicted 2,555 driver NCVs in the promoters of 813 genes across 20 cancer-types. These genes are enriched in cancer-related gene ontologies, essential genes, and genes associated with cancer prognosis. We found that 765 candidate driver NCVs alter transcriptional activity, 510 lead to differential binding of TF-cofactor regulatory complexes, and that they primarily impact the binding of ETS factors. Finally, we show that different NCVs within a promoter often affect transcriptional activity through shared mechanisms. Our integrated computational and experimental approach shows that cancer NCVs are widespread and that ETS factors are commonly disrupted.

cancer biology↗

bioRxiv2022

Inflammation and neuronal gene expression changes differ in early vs late chronic traumatic encephalopathy brain

Our understanding of the molecular underpinnings of chronic traumatic encephalopathy (CTE) and its associated pathology in post-mortem brain is incomplete. Factors including years of play and genetic risk variants influence the extent of tau pathology associated with disease expression, but how these factors affect gene expression, and whether those effects are consistent across the development of disease, is unknown. To address these questions, we conducted an analysis of the largest mRNASeq whole-transcriptome dataset available to date. We examined the genes and biological processes associated with disease by comparing individuals with CTE with control individuals with a history of repetitive head impacts that lack CTE pathology. We then identified genes and biological processes associated with total years of play as a measure of exposure, amount of tau pathology present at time of death, and the presence of APOE and TMEM106B risk variants. Samples were stratified into low and high pathology groups based on extent of tau pathology and years of play to model early vs late changes in response to exposure, and the relative effects associated with these factors were compared between these groups. Substantial gene expression changes were associated with severe disease for most of these factors, primarily implicating diverse, highly increased neuroinflammatory and neuroimmune processes. In contrast, low exposure groups had many fewer genes and processes implicated and show striking differences for some factors when compared with severe disease. Specifically, gene expression associated with amount of tau pathology showed a nearly perfect inverse relationship when compared between these two groups. Together, these results suggest the early disease process may differ substantially from that observed in late stages, that total years of play and tau pathology influence disease expression differently, and that related pathology-modifying risk variants may do so via distinct biological pathways.

genomics↗

bioRxiv2022

Holobiont transcriptomes for the critically endangered staghorn coral (Acropora cervicornis) from two environmentally distinct sites on Turneffe Atoll, Belize

Historically, staghorn coral (Acropora cervicornis) was a preeminent reef-builder in the Caribbean and Tropical Western Atlantic, where it constructed extensive thickets at 5-20 m depth that supported diverse ecosystems and provided coastal populations with food, storm protection, and income from tourism. In recent decades, A. cervicornis declined precipitously, up to 97% in some localities. To reverse its decline, widespread efforts are underway to characterize the phenotypic and genetic diversity of persisting populations with the goal of restoring them to historical levels by out-planting nursery grown specimens. To support this target, we developed transcriptomes for two A. cervicornis populations located in Turneffe Atoll Marine Reserve, Belize. These populations experience significantly different temperatures, light levels and water currents, and they harbor individuals that differ in key phenotypes. Because differentiating the gene activity of diverse taxa--i.e., coral host, algal photosymbiont, plus associated eukaryotes, bacteria, archaea, and viruses-- is critical to understanding the function of the coral holobiont, we developed a pipeline for parsing transcripts by taxon. Separate transcriptomes for each population contain complete representatives for >96% of 978 conserved metazoan single copy orthologs. The taxonomic breakdown of transcripts differed between sites, with more bacterial transcripts recovered from Calabash Caye and more symbiont transcripts from Blackbird Caye. The assembled transcriptomes will facilitate gene expression studies and in silico cloning from this endangered coral.

genomics↗