| Experiment Id | GSE158595 | Name | E4F1 coordinates pyruvate metabolism and the activity of the elongator complex to ensure protein translation fidelity during neuronal development |
| Experiment Type | RNA-Seq | Study Type | WT vs. Mutant |
| Source | GEO | Curation Date | 2023-07-18 |
| description | The Leigh syndrome is a severe inborn neurodegenerative encephalopathy that is commonly associated with pyruvate metabolism defects. The transcription factor E4F1, a key regulator of the pyruvate dehydrogenase complex (PDC), was previously found to be mutated in Leigh syndrome patients but the molecular mechanisms leading to cell death in E4F1-deficient neurons remain unknown. Here, we show that E4F1 coordinates a transcriptional program involved in AcetylCoenzyme A (AcCoA) production by the PDC and its utilization by the Elongator complex to acetylate tRNAs and thereby enhance protein translation fidelity in the central nervous system. E4F1 directly regulates the expression of Dlat and Elp3, two genes encoding key subunits of the PDC and the Elongator complex. Consistently, genetic inactivation of E4f1 in neurons during mouse embryonic development decreased the activity of the PDC and of the Elongator complex, resulting in impaired tRNAs editing and the induction of an endoplasmic reticulum (ER) stress / unfolded protein response (UPR) that led to neuronal cell death and microcephaly. Impaired expression of ELP3 and activation of an ATF-driven UPR response was also observed in fibroblasts from Leigh syndrome patients harboring a homozygous E4F1K144Q mutation. Our findings identify a novel crosstalk between pyruvate metabolism and the regulation of protein translation that is perturbed in Leigh syndrome patients. mRNA profiles of 3 brains of E14.5 wild type (WT) and E4f1 KO (KO) mice. |
| notes | bioRxiv preprint: https://doi.org/10.1101/2022.12.19.521032 |
