EP400NL is required for cMyc-mediated PD-L1 gene activation by forming a transcriptional coactivator complex

Abstract

ABSTRACTEP400 is an ATP-dependent chromatin remodeling enzyme that has been implicated in DNA double-strand break repair and transcription regulation including Myc-dependent gene expression. We previously showed that the N-terminal domain of EP400 increases the efficacy of chemotherapeutic drugs against cancer cells. As the EP400 N-terminal-Like (EP400NL) gene resides next to the EP400 gene locus prompted us to investigate whether EP400NL also plays a similar role in epigenetic transcriptional regulation to the full-length EP400 protein. We found that EP400NL forms a human NuA4-like chromatin remodelling complex that lacks both the TIP60 histone acetyltransferase and EP400 ATPase. However, this EP400NL complex displays H2A.Z deposition activity on a chromatin template comparable to the human NuA4 complex, suggesting another associated ATPase such as BRG1 or RuvBL1/RuvBL2 catalyses the reaction. We also demonstrated that the transcriptional coactivator function of EP400NL is required for cMyc and IFNγ-mediated PD-L1 gene activation. Collectively, our studies show that EP400NL plays a role as a transcription coactivator for cMyc-mediated gene expression and provides a potential target to modulate PD-L1 expression in cancer immunotherapy.