title: Dissecting genetics of cutaneous miRNA in a mouse model of an autoimmune blistering disease.
abstract: BACKGROUND
  MicroRNAs (miRNAs) are small endogenous non-coding RNAs that control genes at post-transcriptional level. They are essential for development and tissue differentiation, and such altered miRNA expression patterns are linked to the pathogenesis of inflammation and cancer. There is evidence that miRNA expression is genetically controlled similar to the transcription of protein-coding genes and previous studies identified quantitative trait loci (QTL) for miRNA expression in the liver. So far, little attention has been paid to miRNA expression in the skin. Moreover, epistatic control of miRNA expression remains unknown. In this study, we characterize genetic regulation of cutaneous miRNA and their correlation with skin inflammation using a previously established murine autoimmune-prone advanced intercross line.
  
  
  RESULTS
  We identified in silico 42 eQTL controlling the expression of 38 cutaneous miRNAs and furthermore found two chromosomal hot-spots on chromosomes 2 and 8 that control the expression of multiple miRNAs. Moreover, for 8 miRNAs an interacting effect from pairs of SNPs was observed. Combining the constraints on genes from the statistical interaction of their loci and further using curated protein interaction networks, the number of candidate genes for association of miRNAs was reduced to a set of several genes. A cluster analysis identified miR-379 and miR-223 to be associated with EBA severity/onset, where miR-379 was observed to be associated to loci on chromosome 6.
  
  
  CONCLUSIONS
  The murine advanced intercross line allowed us to identify the genetic loci regulating multiple miRNA in skin. The recurrence of trans-eQTL and epistasis suggest that cutaneous miRNAs are regulated by yet an unexplored complex gene networks. Further, using co-expression analysis of miRNA expression levels we showed that multiple miRNA contribute to multiple pathways that might be involved in pathogenesis of autoimmune skin blistering disease. Specifically, we provide evidence that miRNA such as miR-223 and miR-379 may play critical role in disease progression and severity.
authors.affiliation: Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany. Yask.Gupta@uksh.de.
authors.forename: Yask
authors.initials: Y
authors.lastname: Gupta
authors.affiliation: Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany. Steffen.Moeller@uksh.de.
authors.forename: Steffen
authors.initials: S
authors.lastname: Möller
authors.affiliation: Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany. witte_mareike@web.de.
authors.forename: Mareike
authors.initials: M
authors.lastname: Witte
authors.affiliation: Max Planck Institute for Evolutionary Biology, Plön, Germany and Institute for Experimental Medicine, University of Kiel, Kiel, Germany. belheouane@evolbio.mpg.de.
authors.forename: Meriem
authors.initials: M
authors.lastname: Belheouane
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany. tanya.sez@gmail.com.
authors.forename: Tanya
authors.initials: T
authors.lastname: Sezin
authors.affiliation: Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany. Misa.Hirose@uksh.de.
authors.forename: Misa
authors.initials: M
authors.lastname: Hirose
authors.affiliation: Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany. Artem.Vorobyev@uksh.de.
authors.forename: Artem
authors.initials: A
authors.lastname: Vorobyev
authors.affiliation: Institute of Molecular Medicine, University of Lübeck, Lübeck, Germany. niesar@imm.uni-luebeck.de.
authors.forename: Felix
authors.initials: F
authors.lastname: Niesar
authors.affiliation: Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany. Julia.Bischof@uksh.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Bischof
authors.affiliation: Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany. Ralf.Ludwig@uksh.de.
authors.forename: Ralf J
authors.initials: RJ
authors.lastname: Ludwig
authors.affiliation: Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany. Detlef.Zillikens@uksh.de.|Department of Dermatology, University of Lübeck, Lübeck, Germany. Detlef.Zillikens@uksh.de.
authors.forename: Detlef
authors.initials: D
authors.lastname: Zillikens
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany. Christian.Sadik@uksh.de.
authors.forename: Christian D
authors.initials: CD
authors.lastname: Sadik
authors.affiliation: Institute of Molecular Medicine, University of Lübeck, Lübeck, Germany. restle@imm.uni-luebeck.de.
authors.forename: Tobias
authors.initials: T
authors.lastname: Restle
authors.affiliation: IKMB, Molecular Cell Biology, Kiel, Germany. r.haesler@mucosa.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Häsler
authors.affiliation: Max Planck Institute for Evolutionary Biology, Plön, Germany and Institute for Experimental Medicine, University of Kiel, Kiel, Germany. baines@evolbio.mpg.de.
authors.forename: John F
authors.initials: JF
authors.lastname: Baines
authors.affiliation: Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany. saleh.ibrahim@uksh.de.
authors.forename: Saleh M
authors.initials: SM
authors.lastname: Ibrahim
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D001768:Blister / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D004843:Epistasis, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D059467:Transcriptome
chemical_list: D035683:MicroRNAs