Poised PABP-RNA hubs implement signal-dependent mRNA decay in development.
Miha ModicKlara KuretSebastian SteinhauserRupert FarawayEmiel van GenderenRuiz De Los Mozos IgorJona NovljanŽiga VičičFlora C Y LeeDerk Ten BergeNicholas M LuscombeJernej UlePublished in: Nature structural & molecular biology (2024)
Signaling pathways drive cell fate transitions largely by changing gene expression. However, the mechanisms for rapid and selective transcriptome rewiring in response to signaling cues remain elusive. Here we use deep learning to deconvolve both the sequence determinants and the trans-acting regulators that trigger extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase kinase (MEK)-induced decay of the naive pluripotency mRNAs. Timing of decay is coupled to embryo implantation through ERK-MEK phosphorylation of LIN28A, which repositions pLIN28A to the highly A+U-rich 3' untranslated region (3'UTR) termini of naive pluripotency mRNAs. Interestingly, these A+U-rich 3'UTR termini serve as poly(A)-binding protein (PABP)-binding hubs, poised for signal-induced convergence with LIN28A. The multivalency of AUU motifs determines the efficacy of pLIN28A-PABP convergence, which enhances PABP 3'UTR binding, decreases the protection of poly(A) tails and activates mRNA decay to enable progression toward primed pluripotency. Thus, the signal-induced convergence of LIN28A with PABP-RNA hubs drives the rapid selection of naive mRNAs for decay, enabling the transcriptome remodeling that ensures swift developmental progression.
Keyphrases
- binding protein
- gene expression
- cell fate
- signaling pathway
- pi k akt
- high glucose
- diabetic rats
- deep learning
- protein kinase
- hiv infected
- transcription factor
- cell proliferation
- drug induced
- tyrosine kinase
- dna methylation
- machine learning
- endothelial cells
- endoplasmic reticulum stress
- artificial intelligence
- antiretroviral therapy