Search results for "Reprogramming"
showing 10 items of 113 documents
Transcriptional Mechanisms of Proneural Factors and REST in Regulating Neuronal Reprogramming of Astrocytes
2015
Summary Direct lineage reprogramming induces dramatic shifts in cellular identity, employing poorly understood mechanisms. Recently, we demonstrated that expression of Neurog2 or Ascl1 in postnatal mouse astrocytes generates glutamatergic or GABAergic neurons. Here, we take advantage of this model to study dynamics of neuronal cell fate acquisition at the transcriptional level. We found that Neurog2 and Ascl1 rapidly elicited distinct neurogenic programs with only a small subset of shared target genes. Within this subset, only NeuroD4 could by itself induce neuronal reprogramming in both mouse and human astrocytes, while co-expression with Insm1 was required for glutamatergic maturation. Cu…
Single Cell RT-PCR on Mouse Embryos: A General Approach for Developmental Biology
2010
Preimplantation development is a complicated process, which involves many genes. We have investigated the expression patterns of 17 developmentally important genes and isoforms in early mouse embryos as well as in single cells of the mouse embryo. The comparison is an excellent example for showing the importance of studying heterogeneity among cell populations on the RNA level, which is being increasingly addressed in basic research and medical sciences, particularly with a link to diagnostics (e.g. the analysis of circulating tumor cells and their progenitors). The ubiquitously expressed histone variant H3f3a and the transcription factor Pou5f1 generated mRNA-derived products in all analyz…
PCF11 links alternative polyadenylation to formation and spontaneous regression of neuroblastoma
2018
AbstractDiversification at the transcriptome 3’end is an important and evolutionarily conserved layer of gene regulation associated with differentiation and dedifferentiation processes. However the underlying mechanisms and functional consequences are poorly defined. Here, we identify extensive transcriptome-3’end-alterations in neuroblastoma, a tumour entity with a paucity of recurrent somatic mutations and an unusually high frequency of spontaneous regression. Utilising extensive RNAi-screening we reveal the landscape and drivers of transcriptome-3’end-diversification, discovering PCF11 as critical regulator, directing alternative polyadenylation (APA) of hundreds of transcripts including…
Improving mRNA-Based Therapeutic Gene Delivery by Expression-Augmenting 3' UTRs Identified by Cellular Library Screening.
2019
Synthetic mRNA has emerged as a powerful tool for the transfer of genetic information, and it is being explored for a variety of therapeutic applications. Many of these applications require prolonged intracellular persistence of mRNA to improve bioavailability of the encoded protein. mRNA molecules are intrinsically unstable and their intracellular kinetics depend on the UTRs embracing the coding sequence, in particular the 3′ UTR elements. We describe here a novel and generally applicable cell-based selection process for the identification of 3′ UTRs that augment the expression of proteins encoded by synthetic mRNA. Moreover, we show, for two applications of mRNA therapeutics, namely, (1) …
Metabolic Escape Routes of Cancer Stem Cells and Therapeutic Opportunities
2020
Although improvement in early diagnosis and treatment ameliorated life expectancy of cancer patients, metastatic disease still lacks effective therapeutic approaches. Resistance to anticancer therapies stems from the refractoriness of a subpopulation of cancer cells—termed cancer stem cells (CSCs)—which is endowed with tumor initiation and metastasis formation potential. CSCs are heterogeneous and diverge by phenotypic, functional and metabolic perspectives. Intrinsic as well as extrinsic stimuli dictated by the tumor microenvironment (TME)have critical roles in determining cell metabolic reprogramming from glycolytic toward an oxidative phenotype and vice versa, allowing cancer cells to th…
Cancer Stem Cells and Neuroblastoma: Characteristics and Therapeutic Targeting Options
2019
The majority of embryonal tumors or childhood blastomas derive from pluripotent progenitors or fetal stem cells that acquire cancer stem cell (CSC) properties: multipotency, self-renewal ability, metastatic potential, chemoresistance, more pronounced levels of drug transporters, enhanced DNA-damage repair mechanisms, and a quiescent state. Neuroblastoma (NB) is considered a neuroendocrine tumor and is the most common extracranial neoplasm in children. NB pathogenesis has frequently been associated with epigenetic dysregulation and a failure to implement a differentiation program. The origin, characteristics, and isolation of the CSC subpopulation in NB are still incompletely understood, des…
Cell Stress, Metabolic Reprogramming, and Cancer
2018
The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis (1). Mitochondria, beyond being the site of aerobic respiration, are at the crossroads of a variety of metabolic and signaling pathways resulting key regulatory organelles in cell life and death decision. Thus, it is no surprise that genomic, functional, and structural mitochondrial alterations have been associated with cancer and that mitochondria have become a pharmacological target in cancer…
Regulation of T-Cell Immune Responses by Pro-Resolving Lipid Mediators
2021
Both the initiation and the resolution of inflammatory responses are governed by the sequential activation, migration, and control/suppression of immune cells at the site of injury. Bioactive lipids play a major role in the fine-tuning of this dynamic process in a timely manner. During inflammation and its resolution, polymorphonuclear cells (PMNs) and macrophages switch from producing pro-inflammatory prostaglandins and leukotrienes to specialized pro-resolving lipid mediators (SPMs), namely, lipoxins, resolvins, protectins, and maresins, which are operative at the local level to limit further inflammation and tissue injury and restore homeostasis. Accumulating evidences expand now the rol…
Molecular Pathways Implicated in Radioresistance of Glioblastoma Multiforme: What Is the Role of Extracellular Vesicles?
2023
Glioblastoma multiforme (GBM) is a primary brain tumor that is very aggressive, resistant to treatment, and characterized by a high degree of anaplasia and proliferation. Routine treatment includes ablative surgery, chemotherapy, and radiotherapy. However, GMB rapidly relapses and develops radioresistance. Here, we briefly review the mechanisms underpinning radioresistance and discuss research to stop it and install anti-tumor defenses. Factors that participate in radioresistance are varied and include stem cells, tumor heterogeneity, tumor microenvironment, hypoxia, metabolic reprogramming, the chaperone system, non-coding RNAs, DNA repair, and extracellular vesicles (EVs). We direct our a…
Non-specific Effects of Vaccines Illustrated Through the BCG Example: From Observations to Demonstrations
2018
Epidemiological studies regarding many successful vaccines suggest that vaccination may lead to a reduction in child mortality and morbidity worldwide, on a grander scale than is attributable to protection against the specific target diseases of these vaccines. These non-specific effects (NSEs) of the Bacille Calmette-Guérin (BCG) vaccine, for instance, implicate adaptive and innate immune mechanisms, with recent evidence suggesting that trained immunity might be a key instrument at play. Collectively referring to the memory-like characteristics of innate immune cells, trained immunity stems from epigenetic reprogramming that these innate immune cells undergo following exposure to a primary…