Abstract: The present disclosure provides a method of regulating expression of a target polynucleotide in a cell. The method may comprise expressing a system in the cell, wherein the cell comprises a receptor having a ligand binding domain specific for a ligand. The method may comprise contacting the cell with the ligand that binds specifically the ligand binding domain. The system expressed in the cell may comprise a first chimeric polypeptide and a second chimeric polypeptide that are activatable upon the contacting. One of the first and second chimeric polypeptides may comprise a gene modulating polypeptide (GMP) comprising an actuator moiety linked to a cleavage recognition site. The actuator moiety may be capable of regulating the expression of the target polynucleotide in the cell. The other of the first and second chimeric polypeptides may comprise a cleavage moiety capable of cleaving the cleavage recognition site of the GMP.

Abstract: Certain aspects of the present disclosure provides systems, compositions, and methods for regulating expression or activity of an endogenous cytokine of a cell. In some cases, the present disclosure provides a system comprising an actuator moiety capable of complexing with a target gene encoding the endogenous cytokine to regulate expression or activity of the endogenous cytokine. The actuator moiety can be heterologous to the cell. The actuator moiety can be activatable upon exposing the cell to an external stimulus. Upon the exposure of the cell to the external stimulus, the actuator moiety can be activated to regulate expression or activity of the endogenous cytokine.

Abstract: The present disclosure provides a chimeric polypeptide comprising at least one heterologous nuclear export signal linked to an adaptor protein of a receptor. The adaptor protein may be a Linker for Activation of T cell (LAT). The receptor may comprise a chimeric receptor.