Engineering combinatorial and dynamic decoders using synthetic immediate-early genes.

TitleEngineering combinatorial and dynamic decoders using synthetic immediate-early genes.
Publication TypeJournal Article
Year of Publication2020
AuthorsRavindran, PT, Wilson, MZ, Jena, SG, Toettcher, JE
JournalCommun Biol
Date Published2020 Aug 13
KeywordsAnimals, DNA Damage, Extracellular Signal-Regulated MAP Kinases, Gene Expression Regulation, Genes, Immediate-Early, Genes, Synthetic, Genetic Engineering, Kinetics, Mice, Mitogens, NIH 3T3 Cells, Proto-Oncogene Proteins c-fos, Signal Transduction, Transcription, Genetic

<p>Many cell- and tissue-level functions are coordinated by intracellular signaling pathways that trigger the expression of context-specific target genes. Yet the input-output relationships that link pathways to the genes they activate are incompletely understood. Mapping the pathway-decoding logic of natural target genes could also provide a basis for engineering novel signal-decoding circuits. Here we report the construction of synthetic immediate-early genes (SynIEGs), target genes of Erk signaling that implement complex, user-defined regulation and can be monitored by using live-cell biosensors to track their transcription and translation. We demonstrate the power of this approach by confirming Erk duration-sensing by FOS, elucidating how the BTG2 gene is differentially regulated by external stimuli, and designing a synthetic immediate-early gene that selectively responds to the combination of growth factor and DNA damage stimuli. SynIEGs pave the way toward engineering molecular circuits that decode signaling dynamics and combinations across a broad range of cellular contexts.</p>

Alternate JournalCommun Biol
PubMed ID32792645
PubMed Central IDPMC7426417
Grant ListDP2 EB024247 / EB / NIBIB NIH HHS / United States
F31 AR075398 / AR / NIAMS NIH HHS / United States
DP2EB024247 / NH / NIH HHS / United States