1. Cumulative effects of weakly repressive regulatory regions in the 3' UTR maintain PD-1 expression homeostasis in mammals.
- Author
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Lai, Xiaoqian, Li, Rong, Wang, Panpan, Li, Meng, Xiao, Chenxi, Cao, Qiang, Li, Xin, and Zhao, Wenxue
- Subjects
HOMEOSTASIS ,GENE expression ,RNA-binding proteins ,PROGRAMMED cell death 1 receptors ,GENETIC regulation ,BINDING sites - Abstract
PD-1 has become a common target for cancer treatment. However, the molecular regulation of PD-1 expression homeostasis remains unclear. Here we report the PD-1 3' UTR can dramatically repress gene expression via promoting mRNA decay. Deletion of the PD-1 3' UTR inhibits T cell activity and promotes T-ALL cell proliferation. Interestingly, the robust repression is attributable to cumulative effects of many weak regulatory regions, which we show together are better able to maintain PD-1 expression homeostasis. We further identify several RNA binding proteins (RBPs) that modulate PD-1 expression via the 3' UTR, including IGF2BP2, RBM38, SRSF7, and SRSF4. Moreover, despite rapid evolution, PD-1 3' UTRs are functionally conserved and strongly repress gene expression through many common RBP binding sites. These findings reveal a previously unrecognized mechanism of maintaining PD-1 expression homeostasis and might represent a general model for how small regulatory effects play big roles in regulation of gene expression and biology. Demonstration that the programmed cell death-1 (PD-1) 3' UTR plays a crucial role regulating gene expression by promoting mRNA decay and various RNA binding proteins, including IGF2BP2, RBM38, SRSF7, and SRSF4, regulate PD-1 expression via the 3' UTR. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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