title: Analysis of miRNA and mRNA expression profiles highlights alterations in ionizing radiation response of human lymphocytes under modeled microgravity.
abstract: BACKGROUND
  Ionizing radiation (IR) can be extremely harmful for human cells since an improper DNA-damage response (DDR) to IR can contribute to carcinogenesis initiation. Perturbations in DDR pathway can originate from alteration in the functionality of the microRNA-mediated gene regulation, being microRNAs (miRNAs) small noncoding RNA that act as post-transcriptional regulators of gene expression. In this study we gained insight into the role of miRNAs in the regulation of DDR to IR under microgravity, a condition of weightlessness experienced by astronauts during space missions, which could have a synergistic action on cells, increasing the risk of radiation exposure.
  
  
  RESULTS
  We analyzed miRNA expression profile of human peripheral blood lymphocytes (PBL) incubated for 4 and 24 h in normal gravity (1 g) and in modeled microgravity (MMG) during the repair time after irradiation with 0.2 and 2Gy of γ-rays. Our results show that MMG alters miRNA expression signature of irradiated PBL by decreasing the number of radio-responsive miRNAs. Moreover, let-7i*, miR-7, miR-7-1*, miR-27a, miR-144, miR-200a, miR-598, miR-650 are deregulated by the combined action of radiation and MMG. Integrated analyses of miRNA and mRNA expression profiles, carried out on PBL of the same donors, identified significant miRNA-mRNA anti-correlations of DDR pathway. Gene Ontology analysis reports that the biological category of "Response to DNA damage" is enriched when PBL are incubated in 1 g but not in MMG. Moreover, some anti-correlated genes of p53-pathway show a different expression level between 1 g and MMG. Functional validation assays using luciferase reporter constructs confirmed miRNA-mRNA interactions derived from target prediction analyses.
  
  
  CONCLUSIONS
  On the whole, by integrating the transcriptome and microRNome, we provide evidence that modeled microgravity can affects the DNA-damage response to IR in human PBL.
authors.affiliation: Dipartimento di Biologia, Università degli Studi di Padova, Padova, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Girardi
authors.forename: Cristiano
authors.initials: C
authors.lastname: De Pittà
authors.forename: Silvia
authors.initials: S
authors.lastname: Casara
authors.forename: Gabriele
authors.initials: G
authors.lastname: Sales
authors.forename: Gerolamo
authors.initials: G
authors.lastname: Lanfranchi
authors.forename: Lucia
authors.initials: L
authors.lastname: Celotti
authors.forename: Maddalena
authors.initials: M
authors.lastname: Mognato
mesh_terms: D018480:Astronauts; D004249:DNA Damage; D020869:Gene Expression Profiling; D006801:Humans; D008214:Lymphocytes / Q000528:radiation effects*; D035683:MicroRNAs / Q000032:analysis* / Q000096:biosynthesis; D012333:RNA, Messenger / Q000032:analysis* / Q000096:biosynthesis; D011839:Radiation, Ionizing; D013026:Space Flight; D059467:Transcriptome; D014893:Weightlessness
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger