Abstract
BackgroundThe general population is constantly exposed to low levels of radiation through natural, occupational or medical irradiation. Even if the biological effects of low-level radiation have been intensely debated and investigated, the molecular mechanisms underlying the cellular response to low doses remain largely unknown.ResultsThe present study investigated the role of GATA3 protein in the control of the cellular and molecular response of human keratinocytes exposed to a 1 cGy dose of X-rays. Chromatin immunoprecipitation showed GATA3 to be able to bind the promoter of 4 genes responding to a 1 cGy exposure. To go further into the role of GATA3 after ionizing radiation exposure, we studied the cellular and molecular consequences of radiation in GATA3 knock-down cells. Knock-down was obtained by lentiviral-mediated expression of an shRNA targeting the GATA3 transcript in differentiated keratinocytes. First, radiosensitivity was assessed: the toxicity, in terms of immediate survival (with XTT test), associated with 1 cGy radiation was found to be increased in GATA3 knock-down cells. The impact of GATA3 knock-down on the transcriptome of X-ray irradiated cells was also investigated, using oligonucleotide microarrays to assess changes between 3 h and 72 h post-irradiation in normal vs GATA3 knock-down backgrounds; transcriptome response was found to be completely altered in GATA3 knock-down cells, with a strong induction/repression peak 48 h after irradiation. Functional annotation revealed enrichment in genes known to be involved in chaperone activity, TGFβ signalling and stress response.ConclusionTaken together, these data indicate that GATA3 is an important regulator of the cellular and molecular response of epidermal cells to very low doses of radiation.
Highlights
The general population is constantly exposed to low levels of radiation through natural, occupational or medical irradiation
GATA proteins bind to the promoters of 4 genes responding to low-dose radiation We have previously shown that low-dose ionizing radiation (IR) induces a specific gene response in normal human differentiated keratinocytes [5]
To validate the potential involvement of these transcription factors in the co-regulation of the 17 genes, we immunoprecipitated the chromatin of 1 cGy and mock irradiated keratinocytes with anti-GATA1 and anti-GATA3 antibodies
Summary
The general population is constantly exposed to low levels of radiation through natural, occupational or medical irradiation. Even if the biological effects of low-level radiation have been intensely debated and investigated, the molecular mechanisms underlying the cellular response to low doses remain largely unknown. Little is known about the transcription factors involved in this response, especially to very low doses of ionizing radiation To further study this question, we used a bioinformatic strategy to identify candidate transcription factors involved in the regulation of low IR dose responding genes [5]. Validating these putative regulators required a dedicated functional genomics approach, which was the goal of the present study
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