scholarly journals Focusing on the Cell Type Specific Regulatory Actions of NLRX1

2021 ◽  
Vol 22 (3) ◽  
pp. 1316
Author(s):  
Tünde Fekete ◽  
Dóra Bencze ◽  
Eduárd Bíró ◽  
Szilvia Benkő ◽  
Kitti Pázmándi
Keyword(s):  
General Pattern ◽  
Signaling Cascades ◽  
Special Focus ◽  
Cell Type ◽  
Cellular Functions ◽  
Associated Functions ◽  
Cell Type Specific ◽  
Regulatory Effects ◽  
The Given ◽  
Regulatory Properties

Cells utilize a diverse repertoire of cell surface and intracellular receptors to detect exogenous or endogenous danger signals and even the changes of their microenvironment. However, some cytosolic NOD-like receptors (NLR), including NLRX1, serve more functions than just being general pattern recognition receptors. The dynamic translocation between the cytosol and the mitochondria allows NLRX1 to interact with many molecules and thereby to control multiple cellular functions. As a regulatory NLR, NLRX1 fine-tunes inflammatory signaling cascades, regulates mitochondria-associated functions, and controls metabolism, autophagy and cell death. Nevertheless, literature data are inconsistent and often contradictory regarding its effects on individual cellular functions. One plausible explanation might be that the regulatory effects of NLRX1 are highly cell type specific and the features of NLRX1 mediated regulation might be determined by the unique functional activity or metabolic profile of the given cell type. Here we review the cell type specific actions of NLRX1 with a special focus on cells of the immune system. NLRX1 has already emerged as a potential therapeutic target in numerous immune-related diseases, thus we aim to highlight which regulatory properties of NLRX1 are manifested in disease-associated dominant immune cells that presumably offer promising therapeutic solutions to treat these disorders.

scholarly journals Genetic influences on cell type specific gene expression and splicing during neurogenesis elucidate regulatory mechanisms of brain traits

2020 ◽  
Author(s):  
Nil Aygün ◽  
Angela L. Elwell ◽  
Dan Liang ◽  
Michael J. Lafferty ◽  
Kerry E. Cheek ◽  
...  
Keyword(s):  
Gene Expression ◽  
Regulatory Elements ◽  
Regulatory Mechanisms ◽  
Specific Gene ◽  
Cell Type ◽  
Specific Expression ◽  
Risk Variants ◽  
Allele Specific ◽  
Cell Type Specific ◽  
Regulatory Effects

SummaryInterpretation of the function of non-coding risk loci for neuropsychiatric disorders and brain-relevant traits via gene expression and alternative splicing is mainly performed in bulk post-mortem adult tissue. However, genetic risk loci are enriched in regulatory elements of cells present during neocortical differentiation, and regulatory effects of risk variants may be masked by heterogeneity in bulk tissue. Here, we map e/sQTLs and allele specific expression in primary human neural progenitors (n=85) and their sorted neuronal progeny (n=74). Using colocalization and TWAS, we uncover cell-type specific regulatory mechanisms underlying risk for these traits.

scholarly journals Myeloid lncRNA LOUP Mediates Opposing Regulatory Effects of RUNX1 and RUNX1-ETO in t(8;21) AML

Blood ◽  
2021 ◽  
Author(s):  
Bon Q Trinh ◽  
Simone Ummarino ◽  
Yanzhou Zhang ◽  
Alexander K Ebralidze ◽  
Mahmoud A Bassal ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Noncoding Rna ◽  
Gene Activation ◽  
Chromatin Accessibility ◽  
Specific Gene ◽  
Cell Type ◽  
Genome Wide ◽  
Therapeutic Development ◽  
Cell Type Specific ◽  
Regulatory Effects

The mechanism underlying cell type-specific gene induction conferred by ubiquitous transcription factors as well as disruptions caused by their chimeric derivatives in leukemia is not well understood. Here we investigate whether RNAs coordinate with transcription factors to drive myeloid gene transcription. In an integrated genome-wide approach surveying for gene loci exhibiting concurrent RNA- and DNA-interactions with the broadly expressed transcription factor RUNX1, we identified the long noncoding RNA LOUP. This myeloid-specific and polyadenylated lncRNA induces myeloid differentiation and inhibits cell growth, acting as a transcriptional inducer of the myeloid master regulator PU.1. Mechanistically, LOUP recruits RUNX1 to both the PU.1 enhancer and the promoter, leading to the formation of an active chromatin loop. In t(8;21) acute myeloid leukemia, wherein RUNX1 is fused to ETO, the resulting oncogenic fusion protein RUNX1-ETO limits chromatin accessibility at the LOUP locus, causing inhibition of LOUP and PU.1 expression. These findings highlight the important role of the interplay between cell type-specific RNAs and transcription factors as well as their oncogenic derivatives in modulating lineage-gene activation and raise the possibility that RNA regulators of transcription factors represent alternative targets for therapeutic development.

scholarly journals Allele-specific analysis reveals exon- and cell-type-specific regulatory effects of Alzheimer's disease-associated genetic variants

2021 ◽  
Author(s):  
Liang He ◽  
Yury Loika ◽  
Alexander Kulminski
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variants ◽  
Mixed Model ◽  
Cell Types ◽  
Cell Type ◽  
Causal Pathways ◽  
Allele Specific ◽  
Cell Type Specific ◽  
Regulatory Effects

Elucidating regulatory effects of Alzheimer's disease (AD)-associated genetic variants is critical for unraveling their causal pathways and understanding the pathology. However, their cell-type-specific regulatory mechanisms in the brain remain largely unclear. Here, we conducted an analysis of allele-specific expression quantitative trait loci (aseQTLs) for 33 AD-associated variants in four brain regions and seven cell types using ~3000 bulk RNA-seq samples and >0.25 million single nuclei. We develop a flexible framework using a hierarchical Poisson mixed model unifying samples in both allelic and genotype-level expression data. We identified 24 AD-associated variants (~73%) that are allele-specific eQTLs (aseQTLs) in at least one brain region. Multiple aseQTLs are region-dependent or exon-specific, such as rs2093760 with CR1, rs7982 with CLU, and rs3865444 with CD33. Notably, the APOE e4 variant reduces APOE expression across all regions, even in healthy controls. In pinpointing the cell types responsible for the observed region-level aseQTLs, we found rs2093760 as an aseQTL of CR1 in oligodendrocytes but not in microglia. Many AD-associated variants are aseQTLs in microglia or monocytes of immune-related genes, including HLA-DQB1, HLA-DQA2, CD33, FCER1G, MS4A6A, SPI1, and BIN1, highlighting the regulatory role of AD-associated variants in the immune response. These findings provide further insights into potential causal pathways and cell types mediating the effects of the AD-associated variants.

scholarly journals Genoppi: an open-source software for robust and standardized integration of proteomic and genetic data

2020 ◽  
Author(s):  
Greta Pintacuda ◽  
Frederik H. Lassen ◽  
Yu-Han H. Hsu ◽  
April Kim ◽  
Jacqueline M. Martín ◽  
...  
Keyword(s):  
Open Source ◽  
Protein Interactions ◽  
General Pattern ◽  
Genetic Data ◽  
Specific Protein ◽  
Specific Interactions ◽  
Cell Type ◽  
Statistical Framework ◽  
Cell Type Specific ◽  
Human Ipsc

AbstractCombining genetic and cell-type-specific proteomic datasets can lead to new biological insights and therapeutic hypotheses, but a technical and statistical framework for such analyses is lacking. Here, we present an open-source computational tool called Genoppi that enables robust, standardized, and intuitive integration of quantitative proteomic results with genetic data. We used Genoppi to analyze sixteen cell-type-specific protein interaction datasets of four proteins (TDP-43, MDM2, PTEN, and BCL2) involved in cancer and neurological disease. Through systematic quality control of the data and integration with published protein interactions, we show a general pattern of both cell-type-independent and cell-type-specific interactions across three cancer and one human iPSC-derived neuronal type. Furthermore, through the integration of proteomic and genetic datasets in Genoppi, our results suggest that the neuron-specific interactions of these proteins are mediating their genetic involvement in neurodevelopmental and neurodegenerative diseases. Importantly, our analyses indicate that human iPSC-derived neurons are a relevant model system for studying the involvement of TDP-43 and BCL2 in amyotrophic lateral sclerosis.

scholarly journals From 1D sequence to 3D chromatin dynamics and cellular functions: a phase separation perspective

2018 ◽  
Author(s):  
Sirui Liu ◽  
Ling Zhang ◽  
Hui Quan ◽  
Hao Tian ◽  
Luming Meng ◽  
...  
Keyword(s):  
Phase Separation ◽  
Chromatin Structure ◽  
Gc Content ◽  
Cell Types ◽  
Cell Type ◽  
Cellular Functions ◽  
Sequence Dependence ◽  
Chromatin Dynamics ◽  
Cell Type Specific ◽  
Different Cell Types

AbstractThe high-order chromatin structure plays a non-negligible role in gene regulation. However, the mechanism for the formation of different chromatin structures in different cells and the sequence dependence of this process remain to be elucidated. As the nucleotide distributions in human and mouse genomes are highly uneven, we identified CGI forest and prairie genomic domains based on CGI density, which better segregates genomic elements along the genome than GC content. The genome is then divided into two sequentially, epigenetically, and transcriptionally distinct regions. These two types of megabase-sized domains spatially segregate, but to a different extent in different cell types. Overall, the forests and prairies gradually segregate from each other in development, differentiation, and senescence. The multi-scale forest-prairie spatial intermingling is cell-type specific and increases in differentiation, thus helps define the cell identity. We propose that the phase separation of the 1D mosaic sequence in space, serving as a potential driving force, together with cell type specific epigenetic marks and transcription factors, shapes the chromatin structure in different cell types and renders them distinct genomic properties. The mosaicity of the genome manifested in terms of alternative forests and prairies of a species could be related to its biological processes such as differentiation, aging and body temperature control.

Beneficial effects of spermidine on cardiovascular health and longevity suggest a cell type-specific import of polyamines by cardiomyocytes

2018 ◽  
Vol 47 (1) ◽  
pp. 265-272 ◽  
Author(s):  
Bengt-Olof Nilsson ◽  
Lo Persson
Keyword(s):  
Cardiovascular Health ◽  
In Vivo Studies ◽  
Special Focus ◽  
Cell Type ◽  
Excitable Cells ◽  
Beneficial Effects ◽  
A Cell ◽  
Cell Type Specific ◽  
Stimulation Of

Abstract Recent and exciting in vivo studies show that supplementation with the polyamine spermidine (Spd) is cardioprotective and prolongs lifespan in both mice and humans. The mechanisms behind Spd-induced cardioprotection are supposed to involve Spd-evoked stimulation of autophagy, mitophagy and mitochondrial respiration and improved the mechano-elastical function of cardiomyocytes. Although cellular uptake of Spd was not characterized, these results suggest that Spd is imported by the cardiomyocytes and acts intracellularly. In the light of these new and thrilling data, we discuss in the present review cellular polyamine import with a special focus on mechanisms that may be relevant for Spd uptake by electrically excitable cells such as cardiomyocytes.

scholarly journals IQGAP1 in Podosome /Invadosome is Involved in the Progression of Glioblastoma Multiforme Depending on the Tumor Status

2016 ◽  
Author(s):  
Deborah Rotoli ◽  
Natalia Pérez-Rodríguez ◽  
Manuel Morales ◽  
María Del Carmen Maeso ◽  
Julio Ávila ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Normal Cell ◽  
Primary Brain Tumor ◽  
Cell Physiology ◽  
Positive Staining ◽  
Cell Type ◽  
Cellular Functions ◽  
Tissue Samples ◽  
Cell Type Specific ◽  
Human Gbm

Glioblastoma multiforme (GBM) is the most frequent and aggressive primary brain tumor. GBM is formed by a very heterogeneous astrocyte population, neurons, neovascularization and infiltrating myeloid cells (microglia and monocyte derived macrophages). The IQGAP1 scaffold protein interacts with components of the cytoskeleton, cell adhesion molecules, and several signaling molecules to regulate cell morphology and motility, cell cycle and other cellular functions. IQGAP1 overexpression and delocalization has been observed in several tumors, suggesting a role for this protein in cell proliferation, transformation and invasion. IQGAP1 has been identified as a marker of amplifying cancer cells in GBMs. To determine the involvement of IQGAP1 in the onco-biology of GBM, we performed immunohistochemical confocal microscopical analysis of the IQGAP1 protein in human GBM tissue samples using cell type-specific markers. IQGAP1 immunostaining and subcellular localization was heterogeneous; the protein was located in the plasma membrane and, at variable levels, in nucleus and/or cytosol). Moreover, IQGAP1 positive staining was found in podosome/invadopodia-like structures. IQGAP1+ staining was observed in neurons (Map2+ cells), in cancer stem cells (CSC; nestin+) and in several macrophages (CD31+ or Iba1+). Our results indicate that the IQGAP1 protein is involved in normal cell physiology and also in oncologic processes.

Soluble VCAM-1 binding to α4 integrins is cell-type specific and activation dependent and is disrupted during apoptosis in T cells

Blood ◽  
2000 ◽  
Vol 95 (2) ◽  
pp. 602-609 ◽  
Author(s):  
David M. Rose ◽  
Pina M. Cardarelli ◽  
Ronald R. Cobb ◽  
Mark H. Ginsberg
Keyword(s):  
Mononuclear Cells ◽  
Atp Synthesis ◽  
Early Event ◽  
Cell Type ◽  
Cellular Functions ◽  
Peripheral Blood Mononuclear ◽  
Cellular Processes ◽  
High Affinity ◽  
Cell Type Specific ◽  
Induced Apoptosis

Soluble vascular cell adhesion molecule-1 (sVCAM-1) is generated during inflammation and can alter lymphocyte functions. The authors report that the binding of sVCAM-1 to 4 integrin-bearing cells is a dynamically regulated, active cellular process. Binding of recombinant sVCAM-1 to 4 integrins on peripheral blood mononuclear cells was cell-type specific. Circulating CD16+ NK cells constitutively bound sVCAM-1 with high affinity, whereas a subpopulation of T-lymphocytes, primarily CD45RO+ (memory), bound sVCAM-1 only after phorbol ester stimulation. sVCAM-1 binding to homogenous stable cell lines was also cell-type specific, and required active cellular processes because it was blocked by the inhibition of ATP synthesis and by Fas-induced apoptosis. Indeed, the loss of high-affinity VCAM-1 binding was an early event in apoptosis. Furthermore, an H-Ras/Raf-initiated signaling pathway also suppressed sVCAM-1 binding to 4β1 integrins. Collectively, these results showed that the capacity of 4 integrins to bind VCAM-1 is actively regulated and that this regulation may control 4 integrin-dependent cellular functions.

scholarly journals A Knockout Mouse Approach Reveals that TCTP Functions as an Essential Factor for Cell Proliferation and Survival in a Tissue- or Cell Type–specific Manner

2007 ◽  
Vol 18 (7) ◽  
pp. 2525-2532 ◽  
Author(s):  
Sung Ho Chen ◽  
Peih-Shan Wu ◽  
Chiang-Hung Chou ◽  
Yu-Ting Yan ◽  
Hsuan Liu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Types ◽  
Cell Type ◽  
Cellular Functions ◽  
Embryonic Fibroblasts ◽  
Embryonic Tissues ◽  
Targeted Gene Disruption ◽  
Specific Manner ◽  
Cell Type Specific ◽  
And Control

Translationally controlled Tumor Protein (TCTP) is an evolutionally highly conserved protein which has been implicated in many cellular functions that are related to cell growth, death, and even the allergic response of the host. To address the physiological roles of TCTP, we generated TCTP knockout mice by targeted gene disruption. Heterozygous mutants appeared to be developmentally normal. However, homozygous mutants (TCTP−/−) were embryonic lethal. TCTP−/− embryos were smaller in size than the control littermates at all postimplantation stages examined. Although TCTP is widely expressed in both extraembryonic and embryonic tissues, the most prominent defect of the TCTP−/− embryo at embryonic stage day 5.5 (E5.5) was in its epiblast, which had a reduced number of cells compared with wild-type controls. The knockout embryos also suffered a higher incidence of apoptosis in epiblast starting about E6.5 and subsequently died around E9.5–10.5 with a severely disorganized structure. Last, we demonstrated that TCTP−/− and control mouse embryonic fibroblasts manifested similar proliferation activities and apoptotic sensitivities to various death stimuli. Taken together, our results suggest that despite that TCTP is widely expressed in many tissues or cell types, it appears to regulate cell proliferation and survival in a tissue- or cell type–specific manner.

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