scholarly journals The glycosaminoglycan-binding domain of PRELP acts as a cell type–specific NF-κB inhibitor that impairs osteoclastogenesis

2009 ◽  
Vol 187 (5) ◽  
pp. 669-683 ◽  
Author(s):  
Nadia Rucci ◽  
Anna Rufo ◽  
Marina Alamanou ◽  
Mattia Capulli ◽  
Andrea Del Fattore ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Basement Membranes ◽  
Binding Domain ◽  
Mitogen Activated Protein Kinase ◽  
Specific Gene ◽  
Cell Type ◽  
Ovariectomized Mice ◽  
A Cell ◽  
Cell Type Specific

Proline/arginine-rich end leucine-rich repeat protein (PRELP) is a glycosaminoglycan (GAG)- and collagen-binding anchor protein highly expressed in cartilage, basement membranes, and developing bone. We observed that PRELP inhibited in vitro and in vivo mouse osteoclastogenesis through its GAG-binding domain (hbdPRELP), involving (a) cell internalization through a chondroitin sulfate– and annexin II–dependent mechanism, (b) nuclear translocation, (c) interaction with p65 nuclear factor κB (NF-κB) and inhibition of its DNA binding, and (d) impairment of NF-κB transcriptional activity and reduction of osteoclast-specific gene expression. hbdPRELP does not disrupt the mitogen-activated protein kinase signaling nor does it impair cell survival. hbdPRELP activity is cell type specific, given that it is internalized by the RAW264.7 osteoclast-like cell line but fails to affect calvarial osteoblasts, bone marrow macrophages, and epithelial cell lines. In vivo, hbdPRELP reduces osteoclast number and activity in ovariectomized mice, underlying its physiological and/or pathological importance in skeletal remodeling.

scholarly journals In vivo cell type-specific gene delivery with retroviral vectors that display single chain antibodies

Gene Therapy ◽  
1999 ◽  
Vol 6 (12) ◽  
pp. 1982-1987 ◽  
Author(s):  
A Jiang ◽  
R Dornburg ◽  
R Dornburg
Keyword(s):  
Gene Delivery ◽  
Retroviral Vectors ◽  
Specific Gene ◽  
Cell Type ◽  
Single Chain ◽  
Single Chain Antibodies ◽  
Cell Type Specific

Gene therapy can target mutations such as BRAF, which have been shown to make tumors more susceptible to autophagy suppression

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Signaling Pathways ◽  
Chemotherapy Resistance ◽  
Effective Strategy ◽  
Cell Type ◽  
Normal Cells ◽  
A Cell ◽  
Cell Type Specific ◽  
Catabolic Process ◽  
Specific Impact

Autophagy is a double-edged sword in cancer, and numerous aspects should be taken into account before deciding on the most effective strategy to target the process. The fact that several clinical studies are now ongoing does not mean that the patient group that may benefit from autophagy-targeting medicines has been identified. Autophagy inhibitors that are more potent and specialized, as well as autophagy indicators, are also desperately required. The fact that these inhibitors only work against tumors that rely on autophagy for survival (RAS mutants) makes it difficult to distinguish them from tumors that continue to develop even when autophagy is absent. Furthermore, mutations such as BRAF have been shown to make tumors more susceptible to autophagy suppression, suggesting that targeting such tumours may be a viable strategy for overcoming their chemotherapy resistance. In the meantime, we are unable to identify if autophagy regulation works in vivo or whether it selectively targets a disease while inflicting injury to other healthy organs and tissues. A cell-type-specific impact appears to be observed with such therapy. As a result, it is just as important to consider the differences between tumors that originate in different organs as it is to consider the signaling pathways that are similar across them. For a therapy or cure to be effective, the proposed intervention must be tailored to the specific needs of each patient.Over the last several years, a growing amount of data has implicated autophagy in a variety of disorders, including cancer. In normal cells, this catabolic process is also required for cell survival and homeostasis. Despite the fact that medications targeting intermediates in the autophagy signaling pathway are being created and evaluated at both the preclinical and clinical levels, given the complicated function of autophagy in cancer, we still have a long way to go in terms of establishing an effective therapeutic approach. This article discusses current tactics for exploiting cancer cells' autophagy dependency, as well as obstacles in the area. We believe that the unanswered concerns raised in this work will stimulate researchers to investigate previously unknown connections between autophagy and other signaling pathways, which might lead to the development of novel, highly specialized autophagy therapies.

scholarly journals Distinct CoREST complexes act in a cell-type-specific manner

2019 ◽  
Author(s):  
Igor Mačinković ◽  
Ina Theofel ◽  
Tim Hundertmark ◽  
Kristina Kovač ◽  
Stephan Awe ◽  
...  
Keyword(s):  
Gene Expression ◽  
Germ Line ◽  
Protein Complexes ◽  
Specific Gene ◽  
S2 Cells ◽  
Cell Type ◽  
Specific Gene Expression ◽  
Genome Wide ◽  
A Cell ◽  
Cell Type Specific

Abstract CoREST has been identified as a subunit of several protein complexes that generate transcriptionally repressive chromatin structures during development. However, a comprehensive analysis of the CoREST interactome has not been carried out. We use proteomic approaches to define the interactomes of two dCoREST isoforms, dCoREST-L and dCoREST-M, in Drosophila. We identify three distinct histone deacetylase complexes built around a common dCoREST/dRPD3 core: A dLSD1/dCoREST complex, the LINT complex and a dG9a/dCoREST complex. The latter two complexes can incorporate both dCoREST isoforms. By contrast, the dLSD1/dCoREST complex exclusively assembles with the dCoREST-L isoform. Genome-wide studies show that the three dCoREST complexes associate with chromatin predominantly at promoters. Transcriptome analyses in S2 cells and testes reveal that different cell lineages utilize distinct dCoREST complexes to maintain cell-type-specific gene expression programmes: In macrophage-like S2 cells, LINT represses germ line-related genes whereas other dCoREST complexes are largely dispensable. By contrast, in testes, the dLSD1/dCoREST complex prevents transcription of germ line-inappropriate genes and is essential for spermatogenesis and fertility, whereas depletion of other dCoREST complexes has no effect. Our study uncovers three distinct dCoREST complexes that function in a lineage-restricted fashion to repress specific sets of genes thereby maintaining cell-type-specific gene expression programmes.

scholarly journals Inducible cell-specific mouse models for paired epigenetic and transcriptomic studies of microglia and astroglia

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Ana J. Chucair-Elliott ◽  
Sarah R. Ocañas ◽  
David R. Stanford ◽  
Victor A. Ansere ◽  
Kyla B. Buettner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Affinity Purification ◽  
Regulation Of Gene Expression ◽  
Cell Types ◽  
Tissue Level ◽  
Cell Phenotype ◽  
Specific Gene ◽  
Cell Type ◽  
A Cell ◽  
Cell Type Specific

AbstractEpigenetic regulation of gene expression occurs in a cell type-specific manner. Current cell-type specific neuroepigenetic studies rely on cell sorting methods that can alter cell phenotype and introduce potential confounds. Here we demonstrate and validate a Nuclear Tagging and Translating Ribosome Affinity Purification (NuTRAP) approach for temporally controlled labeling and isolation of ribosomes and nuclei, and thus RNA and DNA, from specific central nervous system cell types. Analysis of gene expression and DNA modifications in astrocytes or microglia from the same animal demonstrates differential usage of DNA methylation and hydroxymethylation in CpG and non-CpG contexts that corresponds to cell type-specific gene expression. Application of this approach in LPS treated mice uncovers microglia-specific transcriptome and epigenome changes in inflammatory pathways that cannot be detected with tissue-level analysis. The NuTRAP model and the validation approaches presented can be applied to any brain cell type for which a cell type-specific cre is available.

scholarly journals Dual Inactivation of RB and p53 Pathways in RAS-Induced Melanomas

2001 ◽  
Vol 21 (6) ◽  
pp. 2144-2153 ◽  
Author(s):  
Nabeel Bardeesy ◽  
Boris C. Bastian ◽  
Aram Hezel ◽  
Dan Pinkel ◽  
Ronald A. DePinho ◽  
...  
Keyword(s):  
Tumor Cells ◽  
P53 Mutation ◽  
Comparative Genomic ◽  
Cell Type ◽  
Specific Expression ◽  
Rb Pathway ◽  
High Incidence ◽  
A Cell ◽  
Cell Type Specific

ABSTRACT The frequent loss of both INK4a and ARF in melanoma raises the question of which INK4a-ARF gene product functions to suppress melanoma genesis in vivo. Moreover, the high incidence of INK4a-ARF inactivation in transformed melanocytes, along with the lack of p53 mutation, implies a cell type-specific role for INK4a-ARF that may not be complemented by other lesions of the RB and p53 pathways. A mouse model of cutaneous melanoma has been generated previously through the combined effects of INK4a Δ2/3 deficiency (null for INK4a and ARF) and melanocyte-specific expression of activated RAS (tyrosinase-driven H-RASV12G, Tyr-RAS). In this study, we made use of this Tyr-RAS allele to determine whether activated RAS can cooperate withp53 loss in melanoma genesis, whether such melanomas are biologically comparable to those arising inINK4a Δ2/3−/− mice, and whether tumor-associated mutations emerge in the p16INK4a-RB pathway in such melanomas. Here, we report that p53inactivation can cooperate with activated RAS to promote the development of cutaneous melanomas that are clinically indistinguishable from those arisen on theINK4a Δ2/3 null background. Genomewide analysis of RAS-induced p53 mutant melanomas by comparative genomic hybridization and candidate gene surveys revealed alterations of key components governing RB-regulated G1/S transition, including c-Myc, cyclin D1, cdc25a, and p21CIP1. Consistent with the profile of c-Myc dysregulation, the reintroduction of p16INK4a profoundly reduced the growth of Tyr-RASINK4a Δ2/3−/− tumor cells but had no effect on tumor cells derived from Tyr-RAS p53 −/−melanomas. Together, these data validate a role for p53inactivation in melanomagenesis and suggest that both the RB and p53 pathways function to suppress melanocyte transformation in vivo in the mouse.

scholarly journals Effect of Sequence-Directed Nucleosome Disruption on Cell-Type-Specific Repression by α2/Mcm1 in the Yeast Genome

2006 ◽  
Vol 5 (11) ◽  
pp. 1925-1933 ◽  
Author(s):  
Nobuyuki Morohashi ◽  
Yuichi Yamamoto ◽  
Shunsuke Kuwana ◽  
Wataru Morita ◽  
Heisaburo Shindo ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Nucleosome Positioning ◽  
Yeast Genome ◽  
Specific Gene ◽  
Cell Type ◽  
Chromatin Structural ◽  
A Cell ◽  
Cell Type Specific ◽  
Acting In Concert ◽  
Modest Effect

ABSTRACT In Saccharomyces cerevisiae, a-cell-specific genes are repressed in MATα cells by α2/Mcm1, acting in concert with the Ssn6-Tup1 corepressors and the Isw2 chromatin remodeling complex, and nucleosome positioning has been proposed as one mechanism of repression. However, prior studies showed that nucleosome positioning is not essential for repression by α2/Mcm1 in artificial reporter plasmids, and the importance of the nucleosome positioning remains questionable. We have tested the function of positioned nucleosomes through alteration of genomic chromatin at the a-cell-specific gene BAR1. We report here that a positioned nucleosome in the BAR1 promoter is disrupted in cis by the insertion of diverse DNA sequences such as poly(dA) · poly(dT) and poly(dC-dG) · poly(dC-dG), leading to inappropriate partial derepression of BAR1. Also, we show that isw2 mutation causes loss of nucleosome positioning in BAR1 in MATα cells as well as partial disruption of repression. Thus, nucleosome positioning is required for full repression, but loss of nucleosome positioning is not sufficient to relieve repression completely. Even though disruption of nucleosome positioning by the cis- and trans-acting modulators of chromatin has a modest effect on the level of transcription, it causes significant degradation of the α-mating pheromone in MATα cells, thereby affecting its cell type identity. Our results illustrate a useful paradigm for analysis of chromatin structural effects at genomic loci.

Targeted delivery of Chil3/Chil4 siRNA to alveolar macrophages using ternary complexes composed of HMG and oligoarginine micelles

Nanoscale ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 933-943 ◽  
Author(s):  
Moonhwan Choi ◽  
Haeyoon Jeong ◽  
Sol Kim ◽  
Minkyung Kim ◽  
Minhyung Lee ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Delivery System ◽  
Alveolar Macrophages ◽  
Targeted Delivery ◽  
Ternary Complexes ◽  
Specific Gene ◽  
Gene Delivery System ◽  
Cell Type ◽  
A Cell ◽  
Cell Type Specific

Cell-type-specific genes involved in disease can be effective therapeutic targets; therefore, the development of a cell-type-specific gene delivery system is essential.

scholarly journals Monitoring Cell-Type–Specific Gene Expression Using Ribosome Profiling In Vivo During Cardiac Hemodynamic Stress

2019 ◽  
Vol 125 (4) ◽  
pp. 431-448 ◽  
Author(s):  
Shirin Doroudgar ◽  
Christoph Hofmann ◽  
Etienne Boileau ◽  
Brandon Malone ◽  
Eva Riechert ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ribosome Profiling ◽  
Specific Gene ◽  
Cell Type ◽  
Specific Gene Expression ◽  
Hemodynamic Stress ◽  
Cell Type Specific

Cell Type-Specific Gene Expression and Editing Responses to Chronic Fluoxetine Treatment in the In Vivo Mouse Brain and Their Relevance for Stress-Induced Anhedonia

2012 ◽  
Vol 37 (11) ◽  
pp. 2480-2495 ◽  
Author(s):  
Baoman Li ◽  
Lu Dong ◽  
Bing Wang ◽  
Liping Cai ◽  
Ning Jiang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Brain ◽  
Specific Gene ◽  
Cell Type ◽  
Specific Gene Expression ◽  
Fluoxetine Treatment ◽  
Chronic Fluoxetine ◽  
Cell Type Specific

scholarly journals Cell type specific gene expression profiling reveals a role for the complement component C3A in neutrophil migration to tissue damage

2019 ◽  
Author(s):  
Ruth A. Houseright ◽  
Emily E. Rosowski ◽  
Pui Ying Lam ◽  
Sebastien JM Tauzin ◽  
Oscar Mulvaney ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bacterial Infections ◽  
Large Scale ◽  
Affinity Purification ◽  
Neutrophil Migration ◽  
Acute Injury ◽  
Specific Gene ◽  
Cell Type ◽  
Cell Type Specific

AbstractFollowing acute injury, leukocytes rapidly infiltrate into tissues. For efficient recruitment, leukocytes must sense and respond to signals from both from the damaged tissue and from one another. However, the cell type specific transcriptional changes that influence leukocyte recruitment and wound healing have not been well characterized. In this study, we performed a large-scale translating ribosome affinity purification (TRAP) and RNA sequencing screen in larval zebrafish to identify genes differentially expressed by neutrophils, macrophages, and epithelial cells in the context of wounding. We identified the complement pathway and c3a.1, homologous to the C3A component of human complement, as significantly increased in neutrophils in response to a wound. We report that c3a.1−/− zebrafish larvae have impaired neutrophil responses to both tail wounds and localized bacterial infections, as well as increased susceptibility to infection due to a neutrophil-intrinsic function of C3A. We further show that C3A enhances migration of human primary neutrophils to IL-8 and that c3a.1−/− larvae have impaired neutrophil migration in vivo, and a decrease in neutrophil directed migration speed early after wounding. Together, our findings suggest a role for C3A in mediating efficient neutrophil migration to damaged tissues and support the power of TRAP to identify cell-specific changes in gene expression associated with wound-associated inflammation.

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