title: Regulation of cardiac microRNAs by cardiac microRNAs.
abstract: BACKGROUND
  MicroRNAs modestly suppress their direct mRNA targets, and these direct effects are amplified by modulation of gene transcription pathways. Consequently, indirect mRNA modulatory effects of microRNAs to increase or decrease mRNAs greatly outnumber direct target suppressions. Because microRNAs are products of transcription, the potential exists for microRNAs that regulate transcription to regulate other microRNAs.
  
  
  OBJECTIVE
  Determine whether cardiac-expressed microRNAs regulate expression of other cardiac microRNAs, and measure the impact of microRNA-mediated microRNA regulation on indirect regulation of nontarget mRNAs.
  
  
  RESULTS
  Transgenic expression of pre-microRNAs was used to generate mouse hearts expressing 6- to 16-fold normal levels of microRNA (miR)-143, miR-378, and miR-499. Genome-wide mRNA and microRNA signatures were established using deep sequencing; expression profiles provoked by each microRNA were defined. miR-143 suppressed its direct cardiac mRNA target hexokinase 2, but exhibited little indirect target regulation and did not regulate other cardiac microRNAs. Both miR-378 and miR-499 indirectly regulated hundreds of cardiac mRNAs and 15 to 30 cardiac microRNAs. MicroRNA overexpression did not alter normal processing of either transgenic or endogenous cardiac microRNAs, and microRNA-mediated regulation of other microRNAs encoded within parent genes occurred in tandem with parent mRNAs. MicroRNA regulation by miR-378 and miR-499 was stimulus specific, and contributed to observed mRNA downregulation.
  
  
  CONCLUSIONS
  MicroRNAs that modulate cardiac transcription can indirectly regulate other microRNAs. Transcriptional modulation by microRNAs, and microRNA-mediated microRNA regulation, help explain how small direct effects of microRNAs are amplified to generate striking phenotypes.
authors.affiliation: Department of Internal Medicine, Center for Pharmacogenomics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Scot J
authors.initials: SJ
authors.lastname: Matkovich
authors.forename: Yuanxin
authors.initials: Y
authors.lastname: Hu
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
mesh_terms: D000818:Animals; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D017423:Sequence Analysis, RNA; D014158:Transcription, Genetic
chemical_list: C546119:MIRN378 microRNA, mouse; C573190:MIRN499 microRNA, mouse; D035683:MicroRNAs; C532884:MIRN143 microRNA, mouse; D012333:RNA, Messenger
keywords: deep sequencing; genetics; microRNAs; transgenic animals