Nucleic acids are a class of drugs that can modulate gene and protein expression by various mechanisms, namely, RNAi, mRNA degradation by RNase H cleavage, splice modulation, and steric blocking of protein binding or mRNA translation, thus exhibiting immense potential to treat various genetic and rare diseases. Unlike protein-targeted therapeutics, the clinical use of nucleic acids relies on Watson-Crick sequence recognition to regulate aberrant gene expression and impede protein translation. Though promising, targeted delivery remains a bottleneck for the clinical adoption of nucleic acid-based therapeutics.
View Article and Find Full Text PDFMicroRNAs (miRNAs) have been implicated in human disorders, from cancers to infectious diseases. Targeting miRNAs or their target genes with small molecules offers opportunities to modulate dysregulated cellular processes linked to diseases. Yet, predicting small molecules associated with miRNAs remains challenging due to the small size of small molecule-miRNA datasets.
View Article and Find Full Text PDFInteractions between tumor and stromal cells are well known to play prominent roles in progression of pancreatic ductal adenocarcinoma (PDAC). As knowledge of stromal crosstalk in PDAC has evolved, it has become clear that cancer associated fibroblasts can play both tumor promoting and tumor suppressive roles through a combination of paracrine crosstalk and juxtacrine interactions involving direct physical contact. Another major contributor to dismal survival statistics for PDAC is development of resistance to chemotherapy drugs, though less is known about how the acquisition of chemoresistance impacts upon tumor-stromal crosstalk.
View Article and Find Full Text PDFInteractions between tumor and stromal cells are well known to play a prominent roles in progression of pancreatic ductal adenocarcinoma (PDAC). As knowledge of stromal crosstalk in PDAC has evolved, it has become clear that cancer associated fibroblasts can play both tumor promoting and tumor suppressive roles through a combination of paracrine crosstalk and juxtacrine interactions involving direct physical contact. Another major contributor to dismal survival statistics for PDAC is development of resistance to chemotherapy drugs.
View Article and Find Full Text PDFMicroRNAs (miRNAs) are small RNAs that are often dysregulated in many diseases, including cancers. They are highly tissue-specific and stable, thus, making them particularly useful as biomarkers. As the spatial transcriptomics field advances, protocols that enable highly sensitive and spatially resolved detection become necessary to maximize the information gained from samples.
View Article and Find Full Text PDFThe landscape of non-coding mutations in cancer progression and immune evasion is largely unexplored. Here, we identify transcrptome-wide somatic and germline 3' untranslated region (3'-UTR) variants from 375 gastric cancer patients from The Cancer Genome Atlas. By performing gene expression quantitative trait loci (eQTL) and immune landscape QTL (ilQTL) analysis, we discover 3'-UTR variants with cis effects on expression and immune landscape phenotypes, such as immune cell infiltration and T cell receptor diversity.
View Article and Find Full Text PDFSevere COVID-19 leads to widespread transcriptomic changes in the human brain, mimicking diminished cognitive performance. As long noncoding RNAs (lncRNAs) play crucial roles in the regulation of gene expression, identification of the lncRNAs differentially expressed upon COVID-19 may nominate key regulatory nodes underpinning cognitive changes. Here we identify hundreds of lncRNAs differentially expressed in the brains of COVID-19 patients relative to uninfected age/sex-matched controls, many of which are associated with decreased cognitive performance and inflammatory cytokine response.
View Article and Find Full Text PDFGamma peptide nucleic acids (γPNAs) have recently garnered attention in diverse therapeutic and diagnostic applications. Serine and diethylene-glycol-containing γPNAs have been tested for numerous RNA-targeting purposes. Here, we comprehensively evaluated the and efficacy of pH-low insertion peptide (pHLIP)-conjugated serine and diethylene-based γPNAs.
View Article and Find Full Text PDFCoronavirus disease 2019 (COVID-19) remains a significant public health threat due to the ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants to evade the immune system and cause breakthrough infections. Although pathogenic coronaviruses such as SARS-CoV-2 and Middle East respiratory syndrome (MERS)-CoV lead to severe respiratory infections, how these viruses affect the chromatin proteomic composition upon infection remains largely uncharacterized. Here, we use our recently developed integrative DNA And Protein Tagging methodology to identify changes in host chromatin accessibility states and chromatin proteomic composition upon infection with pathogenic coronaviruses.
View Article and Find Full Text PDFCharting microRNA (miRNA) regulation across pathways is key to characterizing their function. Yet, no method currently exists that can quantify how miRNAs regulate multiple interconnected pathways or prioritize them for their ability to regulate coordinate transcriptional programs. Existing methods primarily infer one-to-one relationships between miRNAs and pathways using differentially expressed genes.
View Article and Find Full Text PDFHematological malignancies such as Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and diffuse large B-cell lymphoma (DLBCL) cause significant morbidity in humans. A substantial number of these lymphomas, particularly HL and DLBCLs have poorer prognosis because of their association with Epstein-Barr virus (EBV). Our earlier studies have shown that EBV-encoded nuclear antigen (EBNA2) upregulates programmed cell death ligand 1 in DLBCL and BLs by downregulating microRNA-34a.
View Article and Find Full Text PDFThe tumor microenvironment (TME) is a heterogeneous ecosystem containing cancer cells, immune cells, stromal cells, cytokines, and chemokines which together govern tumor progression and response to immunotherapies. Methyltransferase-like 3 (METTL3), a core catalytic subunit for RNA N-methyladenosine (mA) modification, plays a crucial role in regulating various physiological and pathological processes. Whether and how METTL3 regulates the TME and anti-tumor immunity in non-small-cell lung cancer (NSCLC) remain poorly understood.
View Article and Find Full Text PDFCOVID-19 remains a significant public health threat due to the ability of SARS-CoV-2 variants to evade the immune system and cause breakthrough infections. Although pathogenic coronaviruses such as SARS-CoV-2 and MERS-CoV lead to severe respiratory infections, how these viruses affect the chromatin proteomic composition upon infection remains largely uncharacterized. Here we used our recently developed integrative DNA And Protein Tagging (iDAPT) methodology to identify changes in host chromatin accessibility states and chromatin proteomic composition upon infection with pathogenic coronaviruses.
View Article and Find Full Text PDFMicroRNAs (miRNAs) are small non-coding RNAs first discovered in Caenorhabditis elegans. The let-7 miRNA is highly conserved in sequence, biogenesis and function from C. elegans to humans.
View Article and Find Full Text PDFMol Ther Methods Clin Dev
June 2023
Many diseases, especially cancer, are caused by the abnormal expression of non-coding microRNAs (miRNAs), which regulate gene expression, leading to the development of miRNA-based therapeutics. Synthetic miRNA inhibitors have shown promising efficacy in blocking the activity of aberrant miRNAs that are upregulated in disease-specific pathologies. On the other hand, miRNAs that aid in preventing certain diseases and are reduced in expression in the disease state need different strategies.
View Article and Find Full Text PDFAs coronavirus disease 2019 (COVID-19) and aging are both accompanied by cognitive decline, we hypothesized that COVID-19 might lead to molecular signatures similar to aging. We performed whole-transcriptome analysis of the frontal cortex, a critical area for cognitive function, in individuals with COVID-19, age-matched and sex-matched uninfected controls, and uninfected individuals with intensive care unit/ventilator treatment. Our findings indicate that COVID-19 is associated with molecular signatures of brain aging and emphasize the value of neurological follow-up in recovered individuals.
View Article and Find Full Text PDFThe Keystone Symposium '' was held in Santa Fe, New Mexico from May 1-4, 2022. The symposium was organized by Frank J. Slack, Jörg Vogel, Ivan Martinez and Karyn Schmidt, and brought together scientists working in noncoding RNA biology, therapeutics, and technologies to address mechanistic questions about small regulatory RNAs and facilitate translation of these findings into clinical applications.
View Article and Find Full Text PDFCircular RNAs (circRNA) are a recently described class of RNA molecules that have attracted substantial attention as new components of disease mechanisms and as potential biomarkers in multiple diseases, including cancer. CircRNAs are often highly conserved and exhibit developmental stage- and disease-specific expression. Several studies have reported circRNA expression patterns that are associated with specific cancer types and with patient prognosis.
View Article and Find Full Text PDFSeveral microRNAs have emerged as regulators of pathways that control aging. For example, miR-228 is required for normal lifespan and dietary restriction (DR) mediated longevity through interaction with PHA-4 and SKN-1 transcription factors in Caenorhabditis elegans. miR-229,64,65, and 66, a cluster of microRNAs located adjacent to each other on chromosome III, are in the same family as miR-228, albeit with slight differences in the miR-228 seed sequence.
View Article and Find Full Text PDFRNA therapeutics have emerged as next-generation therapy for the treatment of many diseases. Unlike small molecules, RNA targeted drugs are not limited by the availability of binding pockets on the protein, but rather utilize Watson-Crick (WC) base-pairing rules to recognize the target RNA and modulate gene expression. Antisense oligonucleotides (ASOs) present a powerful therapeutic approach to treat disorders triggered by genetic alterations.
View Article and Find Full Text PDFEvolutionary conservation is a measure of gene functionality that is widely used to prioritise long noncoding RNAs (lncRNA) in cancer research. Intriguingly, while updating our Cancer LncRNA Census (CLC), we observed an inverse relationship between year of discovery and evolutionary conservation. This observation is specific to cancer over other diseases, implying a sampling bias in the selection of lncRNA candidates and casting doubt on the value of evolutionary metrics for the prioritisation of cancer-related lncRNAs.
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