scholarly journals Analyses of Cell Type-Specific Effects of MicroRNA-298 on Native Protein Expression Via Truncated 3’UTR Hold Translational Promise

2021 ◽  
Author(s):  
Ruizhi Wang ◽  
Debomoy K. Lahiri
Keyword(s):  
Protein Expression ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Specific Cell ◽  
Native Protein ◽  
Cell Type ◽  
Protein Levels ◽  
Specific Cell Type ◽  
Cell Type Specific

Abstract Alzheimer’s disease (AD) is marked by neurofibrillary tangles and senile plaques comprising amyloid β (Aβ) peptides. However, specific contributions of different cell types to Aβ deposition remain unknown. Non-coding microRNA (miRNA) play important roles in AD by regulating major proteins involved, like Aβ precursor protein (APP) and β-site APP-cleaving enzyme (BACE1), two key proteins associated with Aβ biogenesis. MiRNAs typically silence protein expression via binding specific sites in 3’- untranslated region (3’UTR) mRNA. MiRNA regulates protein levels in a cell-type specific manner; however, mechanism of miRNA’s variable activities remains unknown. We developed “miRNA-associated native protein expression” (miRnape) assays to determine a natural "UTR limit" for a miRNA’s function in a particular cell type. We report that miR-298 treatment reduced native APP protein levels in an astrocytic but not in a neuronal cell line. From miR-298’s effects on APP-3’UTR activity and native protein levels, we infer that APP 3’-UTR length could explain the differential miR-298’s activity. Such truncated, but natural, 3’-UTR found in a specific cell type provides an opportunity to regulate native protein levels by particular miRNA. Thus, miRNA’s effect tailoring to a specific cell type bypassing another undesired cell type with a truncated 3’-UTR would potentially advance translational research.

scholarly journals Single nucleus analysis of the chromatin landscape in mouse forebrain development

2017 ◽  
Author(s):  
Sebastian Preissl ◽  
Rongxin Fang ◽  
Yuan Zhao ◽  
Ramya Raviram ◽  
Yanxiao Zhang ◽  
...  
Keyword(s):  
Neuronal Cell ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
Regulatory Sequences ◽  
Specific Cell ◽  
Cell Type ◽  
Tissue Samples ◽  
Forebrain Development ◽  
Cell Type Specific ◽  
Accessible Chromatin

ABSTRACTGenome-wide analysis of chromatin accessibility in primary tissues has uncovered millions of candidate regulatory sequences in the human and mouse genomes1–4. However, the heterogeneity of biological samples used in previous studies has prevented a precise understanding of the dynamic chromatin landscape in specific cell types. Here, we show that analysis of the transposase-accessible-chromatin in single nuclei isolated from frozen tissue samples can resolve cellular heterogeneity and delineate transcriptional regulatory sequences in the constituent cell types. Our strategy is based on a combinatorial barcoding assisted single cell assay for transposase-accessible chromatin5 and is optimized for nuclei from flash-frozen primary tissue samples (snATAC-seq). We used this method to examine the mouse forebrain at seven development stages and in adults. From snATAC-seq profiles of more than 15,000 high quality nuclei, we identify 20 distinct cell populations corresponding to major neuronal and non-neuronal cell-types in foetal and adult forebrains. We further define cell-type specific cis regulatory sequences and infer potential master transcriptional regulators of each cell population. Our results demonstrate the feasibility of a general approach for identifying cell-type-specific cis regulatory sequences in heterogeneous tissue samples, and provide a rich resource for understanding forebrain development in mammals.

scholarly journals IRIS3: integrated cell-type-specific regulon inference server from single-cell RNA-Seq

2020 ◽  
Vol 48 (W1) ◽  
pp. W275-W286 ◽  
Author(s):  
Anjun Ma ◽  
Cankun Wang ◽  
Yuzhou Chang ◽  
Faith H Brennan ◽  
Adam McDermaid ◽  
...  
Keyword(s):  
Single Cell ◽  
Target Genes ◽  
Complex Diseases ◽  
Specific Cell ◽  
Rna Seq ◽  
Cell Type ◽  
Specific Cell Type ◽  
Cell Type Specific ◽  
Gene Regulatory ◽  
Human And Mouse

Abstract A group of genes controlled as a unit, usually by the same repressor or activator gene, is known as a regulon. The ability to identify active regulons within a specific cell type, i.e., cell-type-specific regulons (CTSR), provides an extraordinary opportunity to pinpoint crucial regulators and target genes responsible for complex diseases. However, the identification of CTSRs from single-cell RNA-Seq (scRNA-Seq) data is computationally challenging. We introduce IRIS3, the first-of-its-kind web server for CTSR inference from scRNA-Seq data for human and mouse. IRIS3 is an easy-to-use server empowered by over 20 functionalities to support comprehensive interpretations and graphical visualizations of identified CTSRs. CTSR data can be used to reliably characterize and distinguish the corresponding cell type from others and can be combined with other computational or experimental analyses for biomedical studies. CTSRs can, therefore, aid in the discovery of major regulatory mechanisms and allow reliable constructions of global transcriptional regulation networks encoded in a specific cell type. The broader impact of IRIS3 includes, but is not limited to, investigation of complex diseases hierarchies and heterogeneity, causal gene regulatory network construction, and drug development. IRIS3 is freely accessible from https://bmbl.bmi.osumc.edu/iris3/ with no login requirement.

MIROR: a method for cell-type specific microRNA occupancy rate prediction

2014 ◽  
Vol 10 (6) ◽  
pp. 1377-1384 ◽  
Author(s):  
Peng Xie ◽  
Yu Liu ◽  
Yanda Li ◽  
Michael Q. Zhang ◽  
Xiaowo Wang
Keyword(s):  
Specific Cell ◽  
Occupancy Rate ◽  
Cell Type ◽  
Specific Cell Type ◽  
Rate Prediction ◽  
Cell Type Specific ◽  
Novel Method

This work provides a novel method to quantitatively predict miRNA–mRNA interactions in a specific cell type.

scholarly journals Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens

2021 ◽  
Author(s):  
Hee-Dae Kim ◽  
Jing Wei ◽  
Tanessa Call ◽  
Nicole Teru Quintus ◽  
Alexander J. Summers ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Current Treatment ◽  
Specific Cell ◽  
Excitatory Synapses ◽  
Cell Type ◽  
Cell Type Specific ◽  
Specific Regulation ◽  
Circuit Function

AbstractDepression is the leading cause of disability and produces enormous health and economic burdens. Current treatment approaches for depression are largely ineffective and leave more than 50% of patients symptomatic, mainly because of non-selective and broad action of antidepressants. Thus, there is an urgent need to design and develop novel therapeutics to treat depression. Given the heterogeneity and complexity of the brain, identification of molecular mechanisms within specific cell-types responsible for producing depression-like behaviors will advance development of therapies. In the reward circuitry, the nucleus accumbens (NAc) is a key brain region of depression pathophysiology, possibly based on differential activity of D1- or D2- medium spiny neurons (MSNs). Here we report a circuit- and cell-type specific molecular target for depression, Shisa6, recently defined as an AMPAR component, which is increased only in D1-MSNs in the NAc of susceptible mice. Using the Ribotag approach, we dissected the transcriptional profile of D1- and D2-MSNs by RNA sequencing following a mouse model of depression, chronic social defeat stress (CSDS). Bioinformatic analyses identified cell-type specific genes that may contribute to the pathogenesis of depression, including Shisa6. We found selective optogenetic activation of the ventral tegmental area (VTA) to NAc circuit increases Shisa6 expression in D1-MSNs. Shisa6 is specifically located in excitatory synapses of D1-MSNs and increases excitability of neurons, which promotes anxiety- and depression-like behaviors in mice. Cell-type and circuit-specific action of Shisa6, which directly modulates excitatory synapses that convey aversive information, identifies the protein as a potential rapid-antidepressant target for aberrant circuit function in depression.

scholarly journals Cell type-specific biogenesis of novel vesicles containing viral products in human cytomegalovirus infection

2020 ◽  
Author(s):  
Samina Momtaz ◽  
Belen Molina ◽  
Luwanika Mlera ◽  
Felicia Goodrum ◽  
Jean M. Wilson
Keyword(s):  
Endothelial Cells ◽  
Human Cytomegalovirus ◽  
Biosynthetic Pathway ◽  
Cell Types ◽  
Endocytic Pathway ◽  
Specific Cell ◽  
Cell Type ◽  
Subcellular Compartment ◽  
Increased Risk ◽  
Cell Type Specific

AbstractHuman cytomegalovirus (HCMV), while highly restricted for the human species, infects an unlimited array of cell types in the host. Patterns of infection are dictated by the cell type infected, but cell type-specific factors and how they impact tropism for specific cell types is poorly understood. Previous studies in primary endothelial cells showed that HCMV infection induces large multivesicular-like bodies that incorporate viral products including dense bodies and virions. Here we define the nature of these large vesicles using a recombinant virus where UL32, encoding the pp150 tegument protein, is fused in frame with green fluorescent protein (GFP, TB40/E-UL32-GFP). Cells were fixed and labeled with antibodies against subcellular compartment markers and imaged using confocal and super-resolution microscopy. In fibroblasts, UL32-GFP-positive vesicles were marked with classical markers of MVBs, including CD63 and lysobisphosphatidic acid (LBPA), both classical MVB markers, as well as the clathrin and LAMP1. Unexpectedly, UL32-GFP-positive vesicles in endothelial cells were not labeled by CD63, and LBPA was completely lost from infected cells. We defined these UL32-positive vesicles in endothelial cells using markers for the cis-Golgi (GM130), lysosome (LAMP1), and autophagy (LC3B). These findings suggest that virus-containing MVBs in fibroblasts are derived from the canonical endocytic pathway and takeover classical exosomal release pathway. Virus containing MVBs in HMVECs are derived from the early biosynthetic pathway and exploit a less characterized early Golgi-LAMP1-associated non-canonical secretory autophagy pathway. These results reveal striking cell-type specific membrane trafficking differences in host pathways that are exploited by HCMV.ImportanceHuman cytomegalovirus (HCMV) is a herpesvirus that, like all herpesvirus, that establishes a life long infection. HCMV remains a significant cause of morbidity and mortality in the immunocompromised and HCMV seropositivity is associated with increased risk vascular disease. HCMV infects many cells in the human and the biology underlying the different patterns of infection in different cell types is poorly understood. Endothelial cells are important target of infection that contribute to hematogenous spread of the virus to tissues. Here we define striking differences in the biogenesis of large vesicles that incorporate virions in fibroblasts and endothelial cells. In fibroblasts, HCMV is incorporated into canonical MVBs derived from an endocytic pathway, whereas HCMV matures through vesicles derived from the biosynthetic pathway in endothelial cells. This work defines basic biological differences between these cell types that may impact the outcome of infection.

scholarly journals Detection of Cell Types Contributing to Cancer From Circulating, Cell-Free Methylated DNA

2021 ◽  
Vol 12 ◽  
Author(s):  
Megan E. Barefoot ◽  
Netanel Loyfer ◽  
Amber J. Kiliti ◽  
A. Patrick McDeed ◽  
Tommy Kaplan ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Types ◽  
Circulating Tumor Dna ◽  
Cancer Diagnostics ◽  
Tissue Homeostasis ◽  
Specific Cell ◽  
Cell Type ◽  
Liquid Biopsies ◽  
Methylated Dna ◽  
Cell Type Specific

Detection of cellular changes in tissue biopsies has been the basis for cancer diagnostics. However, tissue biopsies are invasive and limited by inaccuracies due to sampling locations, restricted sampling frequency, and poor representation of tissue heterogeneity. Liquid biopsies are emerging as a complementary approach to traditional tissue biopsies to detect dynamic changes in specific cell populations. Cell-free DNA (cfDNA) fragments released into the circulation from dying cells can be traced back to the tissues and cell types they originated from using DNA methylation, an epigenetic regulatory mechanism that is highly cell-type specific. Decoding changes in the cellular origins of cfDNA over time can reveal altered host tissue homeostasis due to local cancer invasion and metastatic spread to distant organs as well as treatment responses. In addition to host-derived cfDNA, changes in cancer cells can be detected from cell-free, circulating tumor DNA (ctDNA) by monitoring DNA mutations carried by cancer cells. Here, we will discuss computational approaches to identify and validate robust biomarkers of changed tissue homeostasis using cell-free, methylated DNA in the circulation. We highlight studies performing genome-wide profiling of cfDNA methylation and those that combine genetic and epigenetic markers to further identify cell-type specific signatures. Finally, we discuss opportunities and current limitations of these approaches for implementation in clinical oncology.

scholarly journals Neuronal cell-type-specific alternative splicing: A mechanism for specifying connections in the brain?

Neurogenesis ◽  
2015 ◽  
Vol 2 (1) ◽  
pp. e1122699 ◽  
Author(s):  
Joshua Shing Shun Li ◽  
Grace Ji-eun Shin ◽  
S Sean Millard
Keyword(s):  
Alternative Splicing ◽  
Neuronal Cell ◽  
Cell Type ◽  
Specific Alternative ◽  
Cell Type Specific ◽  
The Brain
Sign in / Sign up

Export Citation Format

Share Document