| Experiment Id | GSE80130 | Name | Deciphering a secondary genetic code in neurons: the role of codon bias in regulating neuronal protein levels and implications for Elongator-mediated neurological disease |
| Experiment Type | transcription profiling by array | Study Type | WT vs. Mutant |
| Source | GEO | Curation Date | 2022-11-02 |
| description | Familial dysautonomia (FD) results from mutation in IKBKAP/ELP1, a gene encoding the scaffolding protein for the Elongator complex. This highly conserved complex is required for the translation of codon-biased genes in lower organisms. Here we investigate whether Elongator serves a similar function in mammalian peripheral neurons, the population devastated in FD. Using codon-biased eGFP sensors, and multiplexing of codon usage with transcriptome and proteome analyses of over 6,000 genes, we identify two categories of genes, as well as specific gene identities that depend on Elongator for normal expression. Moreover, we show that multiple genes in the DNA damage repair pathway are codon-biased, and that with Elongator loss, their misregulation is correlated with elevated levels of DNA damage. These findings link Elongator's function in the translation of codon-biased genes with both the developmental and neurodegenerative phenotypes of FD, and also clarify the increased risk of cancer associated with the disease. Examining the major genetic pathways that require IKAP are hampered by that Ikbkap null mice are embryonic lethal (E10), but can be examined by genome-wide transcriptome analysis of the dorsal root ganglia from Wnt1-Cre;IkbkapLoxP/LoxP E17.5 fetuses (Ikbkap is deleted from the neural crest). Mice homozygous for a floxed allele of Ikbkap (exon 4) were crossed to mice that are heterozygous for this floxed allele and a Wnt1-Cre transgene. Dorsal root ganglia were removed from E17-18 Wnt1-Cre;IkbkapLoxP/LoxP embryos and stored at -80 until RNA was isolated. Five wildtype and three conditional knock-out animals were analyzed for this experiment. |
