Unknown,Transcriptomics,Genomics,Proteomics

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Downregulation of microRNA expression in the lungs of rats exposed to cigarette smoke

ABSTRACT: While microRNAs have extensively been investigated in cancer research, little is known regarding their response to noxious agents in apparently healthy tissues. We analyzed the expression of 484 miRNAs in the lung of rats exposed to environmental cigarette smoke (ECS) for 28 days. ECS downregulated 126 miRNAs (26.0%) at least two-fold and 24 miRNAs more than three-fold. We previously demonstrated that 107 of 4858 genes (2.9%) and 50 of 518 proteins (9.7%) were upregulated by ECS in the same tissue, consistently with the role of microRNAs as negative regulators of gene expression. The most remarkably downregulated microRNAs belonged to the families of let-7, miR-10, miR-26, miR-30, miR-34, miR-99, miR- 122, miR-123, miR-124, miR-125, miR-140, miR-145, miR-146, miR-191, miR-192, miR-219, miR-222, and miR-223, which regulate stress response, apoptosis, proliferation, angiogenesis, and expression of genes. In contrast, miR-294, an inhibitor of transcriptional repressor genes, was upregulated by ECS. There was a strong parallelism in dysregulation of rodent microRNAs and their human homologues, which are often transcribed from genes localized in fragile sites deleted in lung cancer. Five ECS-downregulated microRNAs are known to be affected by single nucleotide polymorphisms. Thus, changes in microRNA expression are an early event following exposure to cigarette smoke. Keywords: microRNAs â¢ gene expression â¢ environmental cigarette smoke SpragueâDawley rats (Harlan Italy, Correzzana, Milan, Italy), weighing 315-320 g, were either exposed to ECS for 4 weeks or kept in filtered air for the same period of time (sham).

ORGANISM(S): Rattus sp.

SUBMITTER: Patrizio Arrigo

PROVIDER: E-GEOD-13260 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Relationships of microRNA expression in mouse lung with age and exposure to cigarette smoke and light.

Izzotti Alberto A Calin George A GA Steele Vernon E VE Croce Carlo M CM De Flora Silvio S

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20090522 9

MicroRNAs provide a formidable tool not only in cancer research but also to investigate physiological mechanisms and to assess the effect of environmental exposures in healthy tissues. Collectively, cigarette smoke and sunlight have been estimated to account for 40% of all human cancers, and not only smoke but also, surprisingly, UV light induced genomic and postgenomic alterations in mouse lung. Here we evaluated by microarray the expression of 484 microRNAs in the lungs of CD-1 mice, including ...[more]

PMID: 19465468

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Project description:miR-132 and miR-212 are structurally-related microRNAs that have been found to exert powerful modulatory effects within the central nervous system (CNS). Notably, these microRNAs are tandomly processed from the same non-coding transcript, and share a common seed sequence: thus it has been difficult to assess the distinct contribution of each microRNA to gene expression within the CNS. Here, we employed a combination of conditional knockout and transgenic mouse models to examine the contribution of the miR-132/212 gene locus to learning and memory, and then to assess the distinct effects that each microRNA has on hippocampal gene expression. Using a conditional deletion approach, we show that miR-132/212 double knockout mice exhibit significant cognitive deficits in spatial memory, recognition memory, and in tests of novel object recognition. Next, we utilized transgenic miR-132 and miR-212 overexpression mouse lines and the miR-132/212 double knockout line explore the distinct effects of these two miRNAs on the transcriptional profile of the hippocampus. Illumina sequencing revealed that miR-132/212 deletion increased the expression of 1,138 genes; Venn analysis showed that 96 of these genes were also downregulated in mice overexpressing miR-132. Of the 58 genes that were decreased in animals overexpressing miR-212, only four of them were also increased in the knockout line. Functional gene ontology analysis of downregulated genes revealed significant enrichment of genes related to synaptic transmission, neuronal proliferation, and morphogenesis, processes known for their roles in learning, and memory formation. These data, coupled with previous studies, firmly establish a role for the miR-132/212 gene locus as a key regulator of cognitive capacity. Further, although miR-132 and miR-212 share a seed sequence, these data indicate that these miRNAs do not exhibit strongly overlapping mRNA targeting profiles, thus indicating that, these two genes may function in a complex, non-redundant manner to shape the transcriptional profile of the CNS. The dysregulation of miR-132/212 expression could contribute to signaling mechanisms that are involved in an array of cognitive disorders Hippocampal mRNA was isolated from CaMKII-Cre::miR-132/212f/f, tTA::miR132, and tTA::miR212 animals, as well as their respective nontransgenic controls. cDNA from six animals was pooled into three independent biological replicates for each. Libraries were prepared according to the Illumina TruSeqTM Sample Preparation Guide and sequenced using an Illumina Genome Analyzer II. Sequences were aligned to the UCSC mm9 reference genome using Bowtie v0.12.7 and custom R scripts. The sequence data have been submitted to the NCBI Short Read Archive with accession number in progress. Relative abundance was measured in Fragments Per Kilobase of exon per Million fragments mapped using Cufflinks v1.2.

Dataset Information

Downregulation of microRNA expression in the lungs of rats exposed to cigarette smoke

Publications

Relationships of microRNA expression in mouse lung with age and exposure to cigarette smoke and light.

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