CHAF1A Blocks Neuronal Differentiation and Promotes Neuroblastoma Oncogenesis via Metabolic Reprogramming
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ABSTRACT:
PROVIDER: PRJNA603348 | ENA |
REPOSITORIES: ENA
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Project description:Neuroblastoma (NB) arises from neural crest cells (NCCs) secondary to a block in differentiation. Retinoic acid (RA) differentiation therapy has limited therapeutic efficacy, and the mechanisms preventing terminal differentiation remain elusive. We found that the chromatin modifier CHAF1A restricts neuronal differentiation and promotes NB oncogenesis. CHAF1A blocks NC differentiation into mature neurons in both human NCCs and zebrafish models. CHAF1A gain-of-function promotes cell malignancy, blocks RA-induced differentiation, and is sufficient to induce NB tumor formation. Mechanistically, CHAF1A blocks NB differentiation by repressing gene expression programs promoting neuronal development and differentiation, and rewiring polyamine metabolism. Targeting polyamine synthesis restores NB sensitivity to RA therapy. Our results demonstrate that CHAF1A critically contributes to NB oncogenesis by blocking neuronal differentiation and reprogramming cell metabolism.
2021-07-20 | GSE144311 | GEO
Project description:Neuroblastoma (NB) arises from oncogenic disruption of neural crest (NC) differentiation. Treatment with retinoic acid (RA) to induce differentiation has improved survival in some NB patients, but not all patients respond, and most NBs eventually develop resistance to RA. Loss of the chromatin modifier chromatin assembly factor 1 subunit p150 (CHAF1A) promotes NB cell differentiation; however, the mechanism by which CHAF1A drives NB oncogenesis has remained unexplored. This study shows that CHAF1A gain-of-function supports cell malignancy, blocks neuronal differentiation in three models (zebrafish NC, human NC, and human NB), and promotes NB oncogenesis. Mechanistically, CHAF1A upregulates polyamine metabolism, which blocks neuronal differentiation and promotes cell cycle progression. Targeting polyamine synthesis promotes NB differentiation and enhances the anti-tumor activity of RA. The authors' results provide insight into the mechanisms that drive NB oncogenesis and suggest a rapidly translatable therapeutic approach (DFMO plus RA) to enhance the clinical efficacy of differentiation therapy in NB patients.
| S-EPMC8498874 | biostudies-literature
Project description:Neuroblastoma-associated mutations in Drosophila Alk peturb neuronal differentiation and promote neuronal survival.
| PRJNA817171 | ENA
Project description:we explored the changes in metabolic gene expression during neuronal differentiation from neural progenitor cells (NPC).
2016-12-11 | GSE75719 | GEO
Project description:RNA-seq for four neuroblastoma samples (Paired-end protocol). Neuroblastoma is a pediatric cancer of the peripheral nervous system in which structural chromosome aberrations are emblematic of aggressive tumors. In this study, we investigated somatic rearrangements in two neuroblastoma cell lines and two primary tumors using paired-end sequencing of mate-pair libraries (SRA accession number ERP001414) and RNA-seq. In one cell line and in the two primary tumors, this approach confirmed the localization of the majority of rearrangements within one or two chromosomes, consistent with the phenomenon of chromothripsis. RNA-seq experiments confirmed expression of several predicted chimeric genes and genes with disrupted exon structure including ALK, NBAS, FHIT, PTPRD and ODZ4. RNA-seq analysis allowed the identification of abnormal transcripts expressed from genomic rearrangements that may be involved in neuroblastoma oncogenesis.
2013-03-03 | E-MTAB-1367 | biostudies-arrayexpress
Project description:Despite the widespread interest in direct neuronal reprogramming, the mechanisms underpinning fate conversion remain largely unknown. Our study revealed a critical time point after which cells either successfully convert into neurons or succumb to cell death. Co-transduction with Bcl-2 greatly improved negotiation of this critical point by faster neuronal differentiation. Surprisingly, mutants with reduced or no affinity for Bax demonstrated that Bcl-2 exerts this effect by an apoptosis-independent mechanism. Consistent with a caspase-independent role, ferroptosis inhibitors potently increased neuronal reprogramming by inhibiting lipid peroxidation occurring during fate conversion. Genome-wide expression analysis confirmed that treatments promoting neuronal reprogramming elicit an anti-oxidative stress response. Importantly, coexpression of Bcl-2 and anti-oxidative treatments lead to an unprecedented improvement in glial-to-neuron conversion after traumatic brain injury in vivo, underscoring the relevance of these pathways in cellular reprograming irrespective of cell type, in vitro and in vivo. We performed gene expression microarray analysis on mouse embryonic fibroblasts transfected with a viral vector for Ascl1 or empty vector. Cells were then cultured in the absence or presence of forskolin
2016-06-29 | E-GEOD-70921 | biostudies-arrayexpress
Project description:Despite the widespread interest in direct neuronal reprogramming, the mechanisms underpinning fate conversion remain largely unknown. Our study revealed a critical time point after which cells either successfully convert into neurons or succumb to cell death. Co-transduction with Bcl-2 greatly improved negotiation of this critical point by faster neuronal differentiation. Surprisingly, mutants with reduced or no affinity for Bax demonstrated that Bcl-2 exerts this effect by an apoptosis-independent mechanism. Consistent with a caspase-independent role, ferroptosis inhibitors potently increased neuronal reprogramming by inhibiting lipid peroxidation occurring during fate conversion. Genome-wide expression analysis confirmed that treatments promoting neuronal reprogramming elicit an anti-oxidative stress response. Importantly, coexpression of Bcl-2 and anti-oxidative treatments lead to an unprecedented improvement in glial-to-neuron conversion after traumatic brain injury in vivo, underscoring the relevance of these pathways in cellular reprograming irrespective of cell type, in vitro and in vivo. We performed gene expression microarray analysis on mouse embryonic fibroblasts transfected with a viral vector for Ascl1 or empty vector. Cells were then cultured in the absence or presence of forskolin
2015-12-11 | E-GEOD-60790 | biostudies-arrayexpress
Project description:Newly generated neurons pass through a series of well-defined developmental stages, which allow them to integrate into existing neuronal circuits. After exit from the cell cycle, postmitotic neurons undergo neuronal migration, axonal elongation, axon pruning, dendrite morphogenesis and synaptic maturation and plasticity. Lack of a global metabolic analysis during early cortical neuronal development led us to explore the role of cellular metabolism and mitochondrial biology during ex vivo differentiation of primary cortical neurons. Unexpectedly, we observed a huge increase in mitochondrial biogenesis. Changes in mitochondrial mass, morphology and function were correlated with the upregulation of the master regulators of mitochondrial biogenesis, TFAM and PGC-1?. Concomitant with mitochondrial biogenesis, we observed an increase in glucose metabolism during neuronal differentiation, which was linked to an increase in glucose uptake and enhanced GLUT3 mRNA expression and platelet isoform of phosphofructokinase 1 (PFKp) protein expression. In addition, glutamate-glutamine metabolism was also increased during the differentiation of cortical neurons. We identified PI3K-Akt-mTOR signalling as a critical regulator role of energy metabolism in neurons. Selective pharmacological inhibition of these metabolic pathways indicate existence of metabolic checkpoint that need to be satisfied in order to allow neuronal differentiation.
| S-EPMC5072427 | biostudies-literature
Project description:Neuroblastoma is a pediatric tumor of the developing sympathetic nervous system. We investigate developmental origins of neuroblastoma, the role of oncogenic MYCN in blocking normal differentiation and evaluate therapeutic interventions to overcome differentiation blocks. Here, we provide single cell expression profiles of IMR5/75-shMYCN cells upon knockdown of MYCN and control.
2020-12-18 | GSE163429 | GEO
Project description:We report on the characterization of ATRX in-frame fusion neuroblastoma and identify that ATRX IFF proteins re-locate from H3K9me3 enriched regions to active chromatin, such as the promoter of neural repressor REST. We further identify that REST is upregulated in ATRX IFF NB and that several neurogenesis and REST target genes are transcriptionally downregulated. Through ChIP-seq analysis, we observe that REST is bound to ATRX IFF Down genes, which have higher levels of H3K27me3. We further show that ATRX in-frame fusion neuroblastoma cells are sensitive to EZH2 inhibitors through de-repression of H3K27me3 bound neuronal function genes, includiing a subset of REST targets.
2019-10-15 | GSE100148 | GEO