title: Epidrug mediated re-expression of miRNA targeting the HMGA transcripts in pituitary cells.
abstract: BACKGROUND
  Transgenic mice overexpressing the high mobility group A (HMGA) genes, Hmga1 or Hmga2 develop pituitary tumours and their overexpression is also a frequent finding in human pituitary adenomas. In some cases, increased expression of HMGA2 but not that of HMGA1 is consequent to genetic perturbations. However, recent studies show that down-regulation of microRNA (miRNA), that contemporaneously target the HMGA1 and HMGA2 transcripts, are associated with their overexpression.
  
  
  RESULTS
  In a cohort of primary pituitary adenoma we determine the impact of epigenetic modifications on the expression of HMGA-targeting miRNA. For these miRNAs, chromatin immunoprecipitations showed that transcript down-regulation is correlated with histone tail modifications associated with condensed silenced genes. The functional impact of epigenetic modification on miRNA expression was determined in the rodent pituitary cell line, GH3. In these cells, histone tail, miRNA-associated, modifications were similar to those apparent in human adenoma and likely account for their repression. Indeed, challenge of GH3 cells with the epidrugs, zebularine and TSA, led to enrichment of the histone modification, H3K9Ac, associated with active genes, and depletion of the modification, H3K27me3, associated with silent genes and re-expression of HMGA-targeting miRNA. Moreover, epidrugs challenges were also associated with a concomitant decrease in hmga1 transcript and protein levels and concurrent increase in bmp-4 expression.
  
  
  CONCLUSIONS
  These findings show that the inverse relationship between HMGA expression and targeting miRNA is reversible through epidrug interventions. In addition to showing a mechanistic link between epigenetic modifications and miRNA expression these findings underscore their potential as therapeutic targets in this and other diseases.
authors.affiliation: Human Disease and Genomics Group, Institute of Science and Technology in Medicine, School of Medicine, Keele University, Stoke-on-Trent, Staffordshire, ST4 7QB, UK.
authors.forename: Mark O
authors.initials: MO
authors.lastname: Kitchen
authors.forename: Kiren
authors.initials: K
authors.lastname: Yacqub-Usman
authors.forename: Richard D
authors.initials: RD
authors.lastname: Emes
authors.forename: Alan
authors.initials: A
authors.lastname: Richardson
authors.forename: Richard N
authors.initials: RN
authors.lastname: Clayton
authors.forename: William E
authors.initials: WE
authors.lastname: Farrell
mesh_terms: D000236:Adenoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D018899:CpG Islands; D003562:Cytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D024003:HMGA Proteins / Q000235:genetics / Q000378:metabolism*; D025743:HMGA2 Protein / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D024003:HMGA Proteins; D025743:HMGA2 Protein; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D035683:MicroRNAs; C012589:trichostatin A; D003562:Cytidine; C009131:pyrimidin-2-one beta-ribofuranoside