Identification of novel radiation-induced p53-dependent transcripts extensively regulated during mouse brain development

Abstract

Ionizing radiation is a potent activator of the tumor suppressor gene p53, which itself regulates the transcription of genes involved in canonical pathways such as the cell cycle, DNA repair and apoptosis as well as other biological processes like metabolism, autophagy, differentiation and development. In this study, we performed a meta-analysis on gene expression data from different in vivo and in vitro experiments to identify a signature of early radiation-responsive genes which were predicted to be predominantly regulated by p53. Moreover, we found that several genes expressed different transcript isoforms after irradiation in a p53-dependent manner. Among this gene signature, we identified novel p53 targets, some of which have not yet been functionally characterized. Surprisingly, in contrast to genes from the canonical p53-regulated pathways, our gene signature was found to be highly enriched during embryonic and post-natal brain development and during in vitro neuronal differentiation. Furthermore, we could show that for a number of genes, radiation-responsive transcript variants were upregulated during development and differentiation, while radiation non-responsive variants were not. This suggests that radiation exposure of the developing brain and immature cortical neurons results in the p53-mediated activation of a neuronal differentiation program. Overall, our results further increase the knowledge of the radiation-induced p53 network of the embryonic brain and provide more evidence concerning the importance of p53 and its transcriptional targets during mouse brain development.

p53 drives premature neuronal differentiation in response to radiation-induced DNA damage during early neurogenesis

“…Thus, our results showed a very dynamic transcriptional response to radiation. Compared to our previous study, in which we identified a radiation-responsive gene signature using microarrays 31 , the large majority of those genes (77 out of 83) were also identified by RNA-seq (Fig. S2c).…”

“…The activation of cell cycle arrest and apoptosis following DNA damage pointed to the involvement of p53 in the early response to radiation 29,31 . Consequently, we hypothesized that genetic inactivation of Trp53 would abrogate the negative effects of radiation on brain development.…”

Convergence and divergence between the transcriptional responses to Zika virus infection and prenatal irradiation

“…5 Also, in our study, we observed a very high overlap between our gene signature, comprising mostly predicted (both established and novel) p53 targets, and genes that were induced in the Magoh +/− mouse model, with no less than 26 out of 55 induced genes from the Magoh +/− model belonging to our 84-gene signature. This is considerably more than the 16 upregulated genes (out of 3434) found to overlap between Magoh +/− mice and ZIKV-infected hNPCs.…”

“…5 This hypothesis was contradicted by a more recent study of the Magoh +/− mice, in which it was convincingly shown that apoptosis of neuronal progenitors was p53-dependent, whereas premature differentiation was not. 13 Therefore, I have reanalyzed the transcriptional profiles of Magoh +/− mice and prenatally irradiated mice (unpublished data).…”

Lung tumors with distinct p53 mutations respond similarly to p53 targeted therapy but exhibit genotype-specific statin sensitivity

“…1C). Eleven known p53 targets (Mdm2, Cdkn1a [p21], Bbc3 [Puma], Ddit4l, Zfp365, Phlda3, Trp53inp, Gtse1, Ccng1, Sesn2, and Slc19a2) (Utrera et al 1998;Lo et al 2001;Bieging et al 2014;Quintens et al 2015) were similarly regulated across genotypes (Fig. 1D [left], E [top]).…”