Glioblastomas (GBs) are incurable brain tumors. The persistence of aggressive stem-like tumor cells after cytotoxic treatments compromises therapeutic efficacy, leading to GBM recurrence. Forcing the GBM cells to irreversibly abandon their aggressive stem-like phenotype may offer an alternative to conventional cytotoxic treatments.
View Article and Find Full Text PDFEmbryonic stem cell (ESC) fate decisions are regulated by a complex circuitry that coordinates gene expression at multiple levels from chromatin to mRNA processing. Recently, ribosome biogenesis and translation have emerged as key pathways that efficiently control stem cell homeostasis, yet the underlying molecular mechanisms remain largely unknown. Here, we identified RSL24D1 as highly expressed in both mouse and human pluripotent stem cells.
View Article and Find Full Text PDFAdult tumors diagnosed as cerebellar glioblastoma (cGBM) are rare and their optimal classification remains to be determined. The aim of this study was to identify subgroups of cGBM based on targeted molecular analysis. cGBM diagnosed between 2003 and 2017 were identified from the French Brain Tumor Database and reviewed according to the WHO 2021 classification.
View Article and Find Full Text PDFThe detection of cancer stem-like cells (CSCs) is mainly based on molecular markers or functional tests giving a posteriori results. Therefore label-free and real-time detection of single CSCs remains a difficult challenge. The recent development of microfluidics has made it possible to perform high-throughput single cell imaging under controlled conditions and geometries.
View Article and Find Full Text PDFRecent evidence suggests that the chimeric protein SETMAR is a factor of interest in cancer, especially in glioblastoma. However, little is known about the expression of this protein in glioblastoma tissues, and no study has been done to assess if SETMAR could be a prognostic and/or diagnostic marker of glioblastoma. We analyzed protein extracts of 47 glioblastoma samples coming from a local and a national cohort of patients.
View Article and Find Full Text PDFRecent findings suggest that ribosomes, the translational machineries, can display a distinct composition depending on physio-pathological contexts. Thanks to outstanding technological breakthroughs, many studies have reported that variations of rRNA modifications, and more particularly the most abundant rRNA chemical modification, the rRNA 2'O-ribose methylation (2'Ome), intrinsically occur in many organisms. In the last 5 years, accumulating reports have illustrated that rRNA 2'Ome varies in human cell lines but also in living organisms (yeast, plant, zebrafish, mouse, human) during development and diseases.
View Article and Find Full Text PDFBackground: Diffuse hemispheric gliomas, H3 G34-mutant (DHG H3G34-mutant) constitute a distinct type of aggressive brain tumors. Although initially described in children, they can also affect adults. The aims of this study were to describe the characteristics of DHG H3G34-mutant in adults and to compare them to those of established types of adult WHO grade IV gliomas.
View Article and Find Full Text PDFGlioblastoma (GBM) is one of the cancers with the worst prognosis, despite huge efforts to understand its unusual heterogeneity and aggressiveness. This is mainly due to glioblastoma stem cells (GSCs), which are also responsible for the frequent tumor recurrence following surgery, chemotherapy or radiotherapy. In this study, we investigate the expression pattern of the anti-apoptotic BCL-xL protein in several GBM cell lines and the role it might play in GSC-enriched tumorspheres.
View Article and Find Full Text PDFBackground: Biopsies in patients with a suspected glioma are occasionally nondiagnostic.
Objective: To explore the utility of molecular testing in this setting by determining whether IDH1 and TERT promoter (pTERT) mutations could be detected in nondiagnostic biopsies from glioma patients.
Methods: Using SNaPshot polymerase chain reaction, we retrospectively assessed IDH1 and pTERT mutation status in nondiagnostic biopsies from 28 glioma patients.
Embryonic stem cells (ESCs) and adult stem cells (ASCs) possess the remarkable capacity to self-renew while remaining poised to differentiate into multiple progenies in the context of a rapidly developing embryo or in steady-state tissues, respectively. This ability is controlled by complex genetic programs, which are dynamically orchestrated at different steps of gene expression, including chromatin remodeling, mRNA transcription, processing, and stability. In addition to maintaining stem cell homeostasis, these molecular processes need to be rapidly rewired to coordinate complex physiological modifications required to redirect cell fate in response to environmental clues, such as differentiation signals or tissue injuries.
View Article and Find Full Text PDFBackground And Objective: Genomic duplications and fusion involving BRAF and KIAA1549 that create fusion proteins with constitutive B-RAF kinase activity are a hallmark of pilocytic astrocytomas (PAs). The detection of KIAA1549-BRAF fusion transcripts is of paramount importance to classify these tumors and to identify patients who could benefit from BRAF inhibitors. In a clinical setting, the available material for molecular analysis from these pediatric tumors is often limited to formalin-fixed paraffin-embedded (FFPE) tissue.
View Article and Find Full Text PDFPurpose Of Review: Although extensively studied for over a decade, gene expression programs established at the epigenetic and/or transcriptional levels do not fully characterize cancer stem cells (CSC). This review will highlight the latest advances regarding the functional relevance of different key post-transcriptional regulations and how they are coordinated to control CSC homeostasis.
Recent Findings: In the past 2 years, several groups have identified master post-transcriptional regulators of CSC genetic programs, including RNA modifications, RNA-binding proteins, microRNAs and long noncoding RNAs.
The generation of induced pluripotent stem cells (iPSC) from adult somatic cells is one of the most remarkable discoveries in recent decades. However, several works have reported evidence of genomic instability in iPSC, raising concerns on their biomedical use. The reasons behind the genomic instability observed in iPSC remain mostly unknown.
View Article and Find Full Text PDFPrevious investigations of the core gene regulatory circuitry that controls the pluripotency of embryonic stem (ES) cells have largely focused on the roles of transcription, chromatin and non-coding RNA regulators. Alternative splicing represents a widely acting mode of gene regulation, yet its role in regulating ES-cell pluripotency and differentiation is poorly understood. Here we identify the muscleblind-like RNA binding proteins, MBNL1 and MBNL2, as conserved and direct negative regulators of a large program of cassette exon alternative splicing events that are differentially regulated between ES cells and other cell types.
View Article and Find Full Text PDFAlternative splicing (AS) is a key process underlying the expansion of proteomic diversity and the regulation of gene expression. Here, we identify an evolutionarily conserved embryonic stem cell (ESC)-specific AS event that changes the DNA-binding preference of the forkhead family transcription factor FOXP1. We show that the ESC-specific isoform of FOXP1 stimulates the expression of transcription factor genes required for pluripotency, including OCT4, NANOG, NR5A2, and GDF3, while concomitantly repressing genes required for ESC differentiation.
View Article and Find Full Text PDFAlternative splicing is a key process underlying the evolution of increased proteomic and functional complexity and is especially prevalent in the mammalian nervous system. However, the factors and mechanisms governing nervous system-specific alternative splicing are not well understood. Through a genome-wide computational and expression profiling strategy, we have identified a tissue- and vertebrate-restricted Ser/Arg (SR) repeat splicing factor, the neural-specific SR-related protein of 100 kDa (nSR100).
View Article and Find Full Text PDFDeciphering the role of alternative splicing in developmental processes relies on the identification of key genes whose expression is controlled by splicing regulators throughout the growth of a whole organism. Modulating the expression levels of five SR proteins in the developing eye of Drosophila melanogaster revealed that these splicing factors induce various phenotypic alterations in eye organogenesis and also affect viability. Although the SR proteins dASF/SF2 and B52 caused defects in ommatidia structure, only B52 impaired normal axonal projections of photoreceptors and neurogenesis in visual ganglia.
View Article and Find Full Text PDFSerine- and arginine-rich (SR) proteins constitute a highly conserved family of pre-mRNA splicing factors that play key roles in the regulation of splice site selection, and thereby in the control of alternative splicing processes. In addition to conserved sequences at the splice junctions, splice site selection also depends upon different sets of auxiliary cis regulatory elements known as exonic and intronic splicing enhancers (ESEs and ISEs) or exonic and intronic silencers (ESSs and ISSs). Specific binding of SR proteins to their cognate splicing enhancers as well as binding of splicing repressor to silencer sequences serve to enhance or inhibit recognition of weak splice sites by the splicing machinery.
View Article and Find Full Text PDFThe prevalence of alternative splicing as a target for alterations leading to human genetic disorders makes it highly relevant for therapy. Here we have used in vitro splicing reactions with different splicing reporter constructs to screen 4,000 chemical compounds for their ability to selectively inhibit spliceosome assembly and splicing. We discovered indole derivatives as potent inhibitors of the splicing reaction.
View Article and Find Full Text PDFPyruvate dehydrogenase (PDH) complex deficiency is a major cause of lactic acidosis and Leigh's encephalomyelopathies in infancy and childhood, resulting in early death in the majority of patients. Most of the molecular defects have been localized in the coding regions of the E1alpha PDH gene. Recently, we identified a novel mutation of the E1alpha PDH gene in a patient with an encephalopathy and lactic acidosis.
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