title: 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.
abstract: MicroRNAs (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.
  
  
  
  A 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.
  
  
  
  A microRNA body atlas for rat and dog was useful in identifying new candidate miRNA biomarkers of organ toxicity in 2 toxicologically relevant species.
authors: Department of Investigative Toxicology, Non Clinical Safety Assessment and Pathology, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, 46285, IN, USA. smithat@lilly.com.
authors: Aaron
authors: A
authors: Smith
authors: Department of TTX Bioinformatics, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, 46285, IN, USA.
authors: John
authors: J
authors: Calley
authors: Department of TTX Bioinformatics, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, 46285, IN, USA.
authors: Sachin
authors: S
authors: Mathur
authors: Department of Discovery and Development Statistics, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, 46285, IN, USA.
authors: Hui-Rong
authors: HR
authors: Qian
authors: Department of Discovery and Development Statistics, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, 46285, IN, USA.
authors: Han
authors: H
authors: Wu
authors: Department of Discovery and Development Statistics, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, 46285, IN, USA.
authors: Mark
authors: M
authors: Farmen
authors: Department of Toxicogenomics, Maastricht University, Universiteitsingel, Maastricht, The Netherlands.
authors: Florian
authors: F
authors: Caiment
authors: National Institute of Environmental Health Sciences, Biostatistics Branch, Durham, NC, USA.
authors: Pierre R
authors: PR
authors: Bushel
authors: Kelly Government Solutions, Research Triangle Park, Durham, NC, 27709, USA.
authors: Jianying
authors: J
authors: Li
authors: Drug Safety Evaluation, Takeda Pharmaceuticals International Company, Deerfield, USA.
authors: Craig
authors: C
authors: Fisher
authors: Drug Safety Evaluation, Takeda Pharmaceuticals International Company, Deerfield, USA.
authors: Patrick
authors: P
authors: Kirby
authors: Molecular Pathology, Takeda Pharmaceuticals International Company, Deerfield, USA.
authors: Erik
authors: E
authors: Koenig
authors: Department of Investigative Pathology, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, 46285, IN, USA.
authors: David G
authors: DG
authors: Hall
authors: Department of Investigative Toxicology, Non Clinical Safety Assessment and Pathology, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, 46285, IN, USA.
authors: David E
authors: DE
authors: Watson
mesh_terms: D000818:Animals; D015415:Biomarkers; D004285:Dogs; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D009928:Organ Specificity / Q000235:genetics; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D014018:Tissue Distribution / Q000235:genetics
chemical_list: D015415:Biomarkers; D035683:MicroRNAs
keywords: Biomarkers; Deep sequencing; Pancreatic toxicity; Tissue enriched; Tissue specific; microRNA