Biology subjects

Rosenthal, S. B.

Publications and source records attributed to Rosenthal, S. B..

6 recordsLinked to original sources

bioRxiv2025

LARP6 regulates the mRNA translation of fibrogenic genes in liver fibrosis

Metabolic syndrome and excessive alcohol consumption result in liver injury and fibrosis, which is characterized by increased collagen production by activated Hepatic Stellate Cells (HSCs). LARP6, an RNA-binding protein, was shown to facilitate collagen production. However, LARP6 expression and functionality as a regulator of fibrosis development in a disease relevant model remains elusive. By using snRNA-sequencing, we show that LARP6 is upregulated mainly in HSCs of liver fibrosis patients. Moreover, LARP6 knockdown in human HSCs suppresses fibrogenic gene expression. By integrating eCLIP analysis and ribosome profiling in HSCs, we show that LARP6 interacts with mature mRNAs comprising over 300 genes, including RNA structural elements within COL1A1, COL1A2, and COL3A1 to regulate mRNA expression and translation. Furthermore, LARP6 knockdown in HSC attenuates fibrosis development in human liver spheroids. Altogether, our results suggest that targeting LARP6 in human HSCs may provide new strategies for anti-fibrotic therapy. HighlightsO_LILARP6 is upregulated in liver fibrosis, mainly in HSCs. C_LIO_LILARP6 knockdown in human HSCs reduces liver fibrosis development. C_LIO_LIOf the hundreds of gene targets, LARP6 interacts most with collagen mRNAs. C_LIO_LILARP6 regulates mRNA translation via interaction with 5UTRs. C_LI

cell biology↗

bioRxiv2022

Cell-associated Transcriptional Alterations in the Retinal of Alzheimer's Disease

Current approaches for studying pathologic changes in the retina associated with Alzheimers Disease (AD) remain heterogeneous, limiting the use of retinal amyloid-beta as a viable biomarker for AD. Transcriptomic profiling of the retina has provided cell-specific insight into AD progression in the brain yet is lacking in the retina. In this study, we implemented a non-biased approach through next generation sequencing to profile frozen archived retinal tissues from autopsy/pathologically confirmed AD and non-diagnosed cases (NonAD). A total of 37,211 nuclei were isolated from frozen retinal tissue punches originating from AD, and 31,326 were isolated from non-diagnosed cases. Gene expression patterns specific to the retinal region and major retinal cell types were represented in both tissue groups. AD-associated genes were differentially expressed in AD retinal glial cells, including microglia. A greater percentage of microglial nuclei from AD retinal nuclei expressed TYRO protein tyrosine kinase-binding protein (TYROBP) compared to nonAD retinal nuclei. However, compared to microglia from single retinal cell datasets from elderly non-diseased individuals, TYROBP expression is highly expressed in the single cell data set, indicating TYROBP transcripts reside within the cytoplasm. However, other AD-associated genes were differentially expressed in AD nuclei such as DOCK2, PICALM, and PLCG2 compared to non-diseased single-cell microglia, implicating a role of these genes in the AD retina. To summarize, we extracted a high number of nuclei from frozen retinal tissue that retain specific gene markers for cell classification and highlighted candidate AD-associated genes in retinal microglia that may be viable in future AD retinal studies.

neuroscience↗

bioRxiv2022

Collagen remodeling dictates pancreatic cancer bioenergetics and outcome through DDR1 activation or degradation

Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic, aggressive cancer that frequently progresses by liver metastasis1. Cancer-associated fibroblasts (CAF), extracellular matrix (ECM), and type I collagen (Col I) support2-5 or restrain PDAC progression and may impede blood supply and nutrient availability6-8. The dichotomous role of the stroma in PDAC, and the mechanisms through which it influences patient survival and enables desmoplastic cancers escape nutrient limitation remain poorly understood. Here we show that matrix metalloprotease (MMP)-cleaved or intact Col I (cCol I and iCol I, respectively) exert opposing effects on PDAC bioenergetics, macropinocytosis (MP), tumor growth and liver metastasis. While cCol I activates DDR1 (discoidin domain receptor-1)-NF-{kappa}B-p62-NRF2 signaling to promote PDAC growth, iCol I triggers DDR1 degradation and restrains PDAC growth. Patients whose tumors are enriched in iCol I and low in DDR1 and NRF2 have improved median survival compared to those enriched in cCol I, DDR1 and NRF2. Inhibition of DDR1-stimulated NF-{kappa}B or mitochondrial biogenesis blocked tumorigenesis in wildtype mice but not in mice expressing MMP-resistant Col I. In summary, the diverse effects of tumor stroma on PDAC growth, metastasis, and patient survival are mediated through the Col I-DDR1-NF-{kappa}B-NRF2-mitochondrial biogenesis pathway, presenting multiple new opportunities for PDAC therapy.

cancer biology↗

bioRxiv2020

NASA GeneLab RNA-Seq Consensus Pipeline: Standardized Processing of Short-Read RNA-Seq Data

With the development of transcriptomic technologies, we are able to quantify precise changes in gene expression profiles from astronauts and other organisms exposed to spaceflight. Members of NASA GeneLab and GeneLab-associated analysis working groups (AWGs) have developed a consensus pipeline for analyzing short-read RNA-sequencing data from spaceflight-associated experiments. The pipeline includes quality control, read trimming, mapping, and gene quantification steps, culminating in the detection of differentially expressed genes. This data analysis pipeline and the results of its execution using data submitted to GeneLab are now all publicly available through the GeneLab database. We present here the full details and rationale for the construction of this pipeline in order to promote transparency, reproducibility and reusability of pipeline data, to provide a template for data processing of future spaceflight-relevant datasets, and to encourage cross-analysis of data from other databases with the data available in GeneLab.

bioinformatics↗

bioRxiv2020

Functional Landscape of SARS-CoV-2 Cellular Restriction

A deficient interferon response to SARS-CoV-2 infection has been implicated as a determinant of severe COVID-19. To identify the molecular effectors that govern interferon control of SARS-CoV-2 infection, we conducted a large-scale gain-of-function analysis that evaluated the impact of human interferon stimulated genes (ISGs) on viral replication. A limited subset of ISGs were found to control viral infection, including endosomal factors that inhibited viral entry, nucleic acid binding proteins that suppressed viral RNA synthesis, and a highly enriched cluster of ER and Golgi-resident ISGs that inhibited viral translation and egress. These included the type II integral membrane protein BST2/tetherin, which was found to impede viral release, and is targeted for immune evasion by SARS-CoV-2 Orf7a protein. Overall, these data define the molecular basis of early innate immune control of viral infection, which will facilitate the understanding of host determinants that impact disease severity and offer potential therapeutic strategies for COVID-19.

microbiology↗

bioRxiv2018

Perturbed functional networks in Alzheimers Disease reveal opposing roles for TGIF and EGR3

While Alzheimers disease (AD) is the most prevalent cause of dementia, complex combinations of the underlying pathologies have led to evolved concepts in clinical and neuropathological criteria in the past decade. Pathological AD can be decomposed into subsets of individuals with significantly different antemortem cognitive decline rates. Using transcriptome as a proxy for functional state, we preselected 414 expression profiles of clinically and neuropathologically confirmed AD subjects and age matched non-demented controls sampled from a large community based neuropathological study. By combining brain tissue specific protein interactome with gene network, we identify functionally distinct composite clusters of genes which reveal extensive changes in expression levels in AD. The average global expression for clusters corresponding to synaptic transmission, metabolism, cell cycle, survival and immune response were downregulated while the upregulated cluster had a large set of uncharacterized pathways and processes that may constitute an AD specific phenotypic signature. We identified four master regulators across all clusters of differentially expressed genes by enrichment analysis including TGIF1 and EGR3. These transcription factors have previously not been associated with AD and were validated in brain tissue samples from an independent AD cohort. We identify TGIF1, a transcriptional repressor as being neuroprotective in AD by activating co-repressors regulating genes critical for DNA repair, maintaining homeostasis and arresting cell cycle. In addition, we show that loss of EGR3 regulation, mediates synaptic deficits by targeting the synaptic vesicle cycle. Collectively, our results highlight the utility of integrating protein interactions with gene perturbations to generate a comprehensive framework for characterizing the alterations in molecular network as applied to AD.

bioinformatics↗