Year: 2024
Type: article
Abstract: Controlling gene expression is useful for many applications, but current methods often require external user inputs, such as the addition of a drug. We present an alternative approach using cell-autonomous triggers based on RNA stem loop structures in the 3' untranslated regions (UTRs) of mRNA. These stem loops are targeted by the RNA binding proteins Regnase-1 and Roquin-1, allowing us to program stimulation-induced transgene regulation in primary human T cells. By incorporating engineered stem loops into the 3' UTRs of transgenes, we achieved transgene repression through Regnase-1 and Roquin-1 activity, dynamic upregulation upon stimulation, and orthogonal tunability. To demonstrate the utility of this system, we employed it to modulate payloads in CAR-T cells. Our findings highlight the potential of leveraging endogenous regulatory machinery in T cells for transgene regulation and suggest RNA structure as a valuable layer for regulatory modulation.
Source: ACS Synthetic Biology
Authors: David Mai, Carly Harro, Aabir Sanyal, Philipp C. Rommel, Neil C. Sheppard, Carl H. June
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Funders: Robert Wood Johnson Foundation, University of Pennsylvania, Parker Institute for Cancer Immunotherapy, Emerson Collective, National Institutes of Health, Perelman School of Medicine, University of Pennsylvania, National Cancer Institute, National Institute of Allergy and Infectious Diseases
OpenAlex ID: W4405095348