title: Systematically dissecting the global mechanism of miRNA functions in mouse pluripotent stem cells.
abstract: BACKGROUND
  MicroRNAs (miRNAs) critically modulate stem cell properties like pluripotency, but the fundamental mechanism remains largely unknown.
  
  
  METHODS
  This study systematically analyzes multiple-omics data and builds a systems physical network including genome-wide interactions between miRNAs and their targets to reveal the systems mechanism of miRNA functions in mouse pluripotent stem cells.
  
  
  RESULTS
  Globally, miRNAs directly repress the pluripotent core factors during differentiation state. Surprisingly, during the pluripotent state, the top important miRNAs do not directly regulate the pluripotent core factors as previously thought, but they only directly target the pluripotent signal pathways and directly repress developmental processes. Furthermore, at the pluripotent state miRNAs predominately repress DNA methyltransferases, the core enzymes for DNA methylation. The decreasing methylation repressed by miRNAs in turn activates the top miRNAs and pluripotent core factors, creating an active circuit system to modulate pluripotency.
  
  
  CONCLUSIONS
  MiRNAs vary their functions with stem cell states. While miRNAs directly repress pluripotent core factors to facilitate differentiation during the differentiation state, they also help stem cells to maintain pluripotency by activating pluripotent cores through directly repressing DNA methylation systems and primarily inhibiting development in the pluripotent state.
authors.affiliation: School of medicine, University of California San Francisco, S-1268, Medical Sciences Building, 513 Parnassus Ave, San Francisco, CA, 94143, USA. anyou.wang@alumni.ucr.edu.
authors.forename: Anyou
authors.initials: A
authors.lastname: Wang
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. qhe@fhcrc.org.
authors.forename: Qianchuan
authors.initials: Q
authors.lastname: He
authors.affiliation: Division of Gynecologic Oncology, Linyi Tumor Hospital, Shandong, 276000, China. zhongy0410@163.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhong
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D019175:DNA Methylation; D030541:Databases, Genetic; D053263:Gene Regulatory Networks; D051379:Mice; D035683:MicroRNAs / Q000032:analysis*; D039904:Pluripotent Stem Cells / Q000502:physiology*
chemical_list: D035683:MicroRNAs