RNA-seq of different tissues from wild-type and C/EBPa ?uORF mutant African turquoise killifish Nothobranchius furzeri
The transcription factor CCAAT/enhancer binding protein alpha (C/EBPa) regulates cell differentiation, proliferation, and function in various tissues, including the liver, adipose tissue, skin, lung, and hematopoietic system. Studies in rats, mice, humans, and chickens have shown that CEBPA mRNA undergoes alternative translation initiation, producing three C/EBPa protein isoforms. Two of these isoforms act as full-length transcription factors with N-terminal transactivation domains and a C-terminal dimerization and DNA-binding domain. The third isoform is an N-terminally truncated variant, translated from a downstream AUG codon. It competes with full-length isoforms for DNA binding, thereby antagonizing their activity. Expression of the truncated C/EBPa isoform depends on the initial translation of a short upstream open reading frame (uORF) in CEBPA mRNA and subsequent re-initiation at a downstream AUG codon, a process stimulated by mTORC1 signaling. We have generated C/EBPa ?uORF mutant Nothobranchius furzeri fish and demonstrated that this genetic modification significantly extended both the median and maximal lifespan and improved the healthspan of males. Comparative transcriptome analysis revealed an upregulation of genes and pathways that are associated with healthspan and lifespan regulation in other species.
The transcription factor CCAAT/enhancer binding protein alpha (C/EBPa) regulates cell differentiation, proliferation, and function in various tissues, including the liver, adipose tissue, skin, lung, and hematopoietic system. Studies in rats, mice, humans, and chickens have shown that CEBPA mRNA undergoes alternative translation initiation, producing three C/EBPa protein isoforms. Two of these isoforms act as full-length transcription factors with N-terminal transactivation domains and a C-terminal dimerization and DNA-binding domain. The third isoform is an N-terminally truncated variant, translated from a downstream AUG codon. It competes with full-length isoforms for DNA binding, thereby antagonizing their activity. Expression of the truncated C/EBPa isoform depends on the initial translation of a short upstream open reading frame (uORF) in CEBPA mRNA and subsequent re-initiation at a downstream AUG codon, a process stimulated by mTORC1 signaling. We have generated C/EBPa ?uORF mutant Nothobranchius furzeri fish and demonstrated that this genetic modification significantly extended both the median and maximal lifespan and improved the healthspan of males. Comparative transcriptome analysis revealed an upregulation of genes and pathways that are associated with healthspan and lifespan regulation in other species.
European Bioinformatics Institute