RRAD, IL4I1, CDKN1A, and SERPINE1 genes are potentially co-regulated by NF-κB and p53 transcription factors in cells exposed to high doses of ionizing radiation [RNA-Seq]

ABSTRACT: Cellular response to ionizing radiation involves activation of the p53-dependent pathways and activation of the atypical NF-?B pathway. Mechanisms of the crosstalk between these two transcriptional networks include (co)regulation of common gene targets. Novel genes potentially (co)regulated by p53 and NF-?B were found using high-throughput genomics screening in human osteosarcoma U2-OS cells irradiated with a high dose (4 and 10 Gy). Radiation-induced expression in cells with silenced TP53 or RELA (coding the p65 NF-?B subunit) genes was analyzed by RNA-Seq while radiation-induced binding of p53 and RelA (p65) in putative regulatory regions was analyzed by ChIP-Seq, then selected candidates were validated by qPCR. A subset of radiation-modulated genes whose expression was affected by silencing of both TP53 and RELA, and a subset of radiation-upregulated genes where radiation stimulated binding of both p53 and RelA were identified. Competition for the same transcriptional coactivators of p53 and NF-?B was the most probable mechanism of a frequent antagonistic effect of the TP53 and RELA silencing. However, this mode of regulation was noted for 3 genes where radiation-induced binding of both p53 and RelA was observed, namely IL4I1, SERPINE1, and CDKN1A. This suggested a possibility of a direct antagonistic (co)regulation by both factors: activation by NF-?B and inhibition by p53 of IL4I1, and activation by p53 and inhibition by NF-?B of CDKN1A and SERPINE1. On the other hand, radiation-induced binding of both p53 and RelA was observed in a putative regulatory region of RRAD gene whose expression was downregulated both by TP53 and RELA silencing, which suggested a possibility of direct (co)activation by both factors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE110762 | GEO | 2018/02/17

REPOSITORIES: GEO