The Rat microRNA body atlas; Evaluation of the microRNA content of rat organs through deep sequencing and characterization of pancreas enriched miRNAs as biomarkers of pancreatic toxicity in the rat and dog

BMC Genomics

Research Article

Hui-Rong Qian¹  Han Wu¹  Mark Farmen¹  David G. Hall²  Aaron Smith³  David E Watson³  Sachin Mathur⁴  John Calley⁴  Florian Caiment⁵  Patrick Kirby⁶  Craig Fisher⁶  Jianying Li⁷  Erik Koenig⁸  Pierre R. Bushel⁹ 

[1] Department of Discovery and Development Statistics, Lilly Research Laboratories, Lilly Corporate Center, 46285, Indianapolis, IN, USA;Department of Investigative Pathology, Lilly Research Laboratories, Lilly Corporate Center, 46285, Indianapolis, IN, USA;Department of Investigative Toxicology, Non Clinical Safety Assessment and Pathology, Lilly Research Laboratories, Lilly Corporate Center, 46285, Indianapolis, IN, USA;Department of TTX Bioinformatics, Lilly Research Laboratories, Lilly Corporate Center, 46285, Indianapolis, IN, USA;Department of Toxicogenomics, Maastricht University, Universiteitsingel, Maastricht, The Netherlands;Drug Safety Evaluation, Takeda Pharmaceuticals International Company, Deerfield, USA;Kelly Government Solutions, Research Triangle Park, 27709, Durham, NC, USA;Molecular Pathology, Takeda Pharmaceuticals International Company, Deerfield, USA;National Institute of Environmental Health Sciences, Biostatistics Branch, Durham, NC, USA;

关键词: microRNA;    Biomarkers;    Deep sequencing;    Tissue specific;    Tissue enriched;    Pancreatic toxicity;   

DOI  :  10.1186/s12864-016-2956-z

 received in 2016-02-19, accepted in 2016-07-20,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundMicroRNAs (miRNA) are ~19–25 nucleotide long RNA molecules that fine tune gene expression through the inhibition of translation or degradation of the mRNA through incorporation into the RNA induced silencing complex (RISC). MicroRNAs are stable in the serum and plasma, are detectable in a wide variety of body fluids, are conserved across veterinary species and humans and are expressed in a tissue specific manner. They can be detected at low concentrations in circulation in animals and humans, generating interest in the utilization of miRNAs as serum and/or plasma based biomarkers of tissue injury. MicroRNA tissue profiling in rodents has been published, but sample an insufficient number of organs of toxicologic interest using microarray or qPCR technologies for miRNA detection. Here we impart an improved rat microRNA body atlas consisting of 21 and 23 tissues of toxicologic interest from male and female Sprague Dawley rats respectively, using Illumina miRNA sequencing. Several of the authors created a dog miRNA body atlas and we collaborated to test miRNAs conserved in rat and dog pancreas in caerulein toxicity studies utilizing both species.ResultsA rich data set is presented that more robustly defines the tissue specificity and enrichment profiles of previously published and undiscovered rat miRNAs. We generated 1,927 sequences that mapped to mature miRNAs in rat, mouse and human from miRBase and discovered an additional 1,162 rat miRNAs as compared to the current number of rat miRNAs in miRBase version 21. Tissue specific and enriched miRNAs were identified and a subset of these miRNAs were validated by qPCR for tissue specificity or enrichment. As an example of the power of this approach, we have conducted rat and dog pancreas toxicity studies and examined the levels of some tissue specific and enriched miRNAs conserved between rat and dog in the serum of each species. The studies demonstrate that conserved tissue specific/enriched miRs-216a-5p, 375-3p, 148a-3p, 216b-5p and 141-3p are candidate biomarkers of pancreatic injury in the rat and dog.ConclusionsA microRNA body atlas for rat and dog was useful in identifying new candidate miRNA biomarkers of organ toxicity in 2 toxicologically relevant species.

【 授权许可】

CC BY   
© The Author(s). 2016