E4F1 COORDINATES PYRUVATE METABOLISM AND THE ACTIVITY OF THE ELONGATOR COMPLEX TO ENSURE TRANSLATION FIDELITY DURING BRAIN DEVELOPMENT
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ABSTRACT:
PROVIDER: PRJNA665736 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12714561_1.fastq.gz | Fastqsanger.gz | |||
| SRR12714561_2.fastq.gz | Fastqsanger.gz | |||
| SRR12714562_1.fastq.gz | Fastqsanger.gz | |||
| SRR12714562_2.fastq.gz | Fastqsanger.gz | |||
| SRR12714563_1.fastq.gz | Fastqsanger.gz |
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Project description:Elongator is a highly conserved protein complex required for transcriptional elongation, intracellular transport and translation. Elongator complex protein 1 (ELP1) is the scaffolding protein of Elongator and is essential for its assembly and stability. Familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy, is caused by a mutation in ELP1 that lead to a tissue-specific reduction of ELP1 protein. Our work to generate a phenotypic mouse model for FD led to the discovery that homozygous deletion of the mouse Elp1 gene leads to embryonic lethality prior to mid-gestation. Given that FD is caused by a reduction, not loss, of ELP1, we generated two new mouse models by introducing different copy numbers of the human FD ELP1 transgene into the Elp1 knockout mouse (Elp1-/-) and observed that human ELP1 expression rescues embryonic development in a dose dependent manner. We then conducted a comprehensive transcriptome analysis in mouse embryos to identify genes and pathways whose expression correlates with the amount of ELP1. We found that ELP1 is essential for the expression of genes responsible for the formation and development of the nervous system. Further, gene length analysis of the differentially expressed genes showed that the loss of Elp1 mainly impacts the expression of long genes and that by gradually restoring Elongator their expression is progressively rescued. Finally, through evaluation of co-expression modules, we identified gene sets with unique expression patterns that depended on ELP1 expression. Overall, this study highlights the crucial role of ELP1 during early embryonic neuronal development and reveals gene networks and biological pathways that are regulated by Elongator.
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Project description:Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5% of all MB patients. Here, by extending our previous analysis to include all protein-coding genes, we discovered and replicated rare germline loss-of-function (LoF) variants across Elongator Complex Protein 1 (ELP1) on 9q31.3 in 15% of pediatric MBSHH cases, thus implicating ELP1 as the most common MB predisposition gene and increasing genetic predisposition to 40% for pediatric MBSHH. Inheritance was verified based on parent-offspring and pedigree analysis, which identified two families with a history of pediatric MB. ELP1-associated MBs were restricted to the molecular SHH subtype and were characterized by universal biallelic inactivation of ELP1 due to somatic loss of chromosome 9q. The majority of ELP1-associated MBs exhibited co-occurring somatic PTCH1 (9q22.32) alterations, suggesting that ELP1-deficiency predisposes to tumor development in combination with constitutive activation of SHH signaling. ELP1 is an essential subunit of the evolutionary conserved Elongator complex, whose primary function is to enable efficient translational elongation through tRNAs modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed that ELP1-associated MBSHH are characterized by a destabilized core Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response (UPR), consistent with deregulation of protein homeostasis due to Elongator-deficiency in model systems. Our findings suggest that genetic predisposition to proteome instability is a previously underappreciated determinant in the pathogenesis of pediatric brain cancer. These results provide strong rationale for further investigating the role of protein homeostasis in other pediatric and adult cancer types and potential opportunities for novel therapeutic interference.
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Project description:The highly conserved Elongator complex is a translational regulator and a subject of growing interest due to its critical role in neurodevelopment, neurological diseases and brain tumors. Clinically relevant mutations have been reported in the catalytic Elp123 subcomplex, while no mutation in the accessory subcomplex Elp456 have been described so far. Here, we identify pathogenic variants of ELP4 and ELP6 in patients with developmental delay, epilepsy as well as intellectual and motor impairment. We use single particle cryo-EM to determine the structures of human and murine Elp456 subcomplexes and reconstitute an active mouse Elongator comprising of all six subunits. We show that patient derived mutations in Elp456 affect the affinity for specific tRNA molecules and diminish the tRNA modification activity of Elongator in vitro as well as in human and murine cells. Modelling the mutations in mice recapitulates the clinical features of the patients and reveals neuropathology that differs from the one caused by previously characterized Elp123 mutations. Altogether, our study demonstrates a direct correlation between Elp4 and Elp6 mutations, reduced Elongator activity and neurological defects. Foremost, our data indicate distinct roles of the Elp123 and Elp456 subcomplexes for different tRNA species, in different cell types and in different key steps during the neurodevelopment of higher organisms.
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