title: The transcription factor Myt3 acts as a pro-survival factor in β-cells.
abstract: OBJECTIVE
  We previously identified the transcription factor Myt3 as specifically expressed in pancreatic islets. Here, we sought to determine the expression and regulation of Myt3 in islets and to determine its significance in regulating islet function and survival.
  
  
  METHODS
  Myt3 expression was determined in embryonic pancreas and adult islets by qPCR and immunohistochemistry. ChIP-seq, ChIP-qPCR and luciferase assays were used to evaluate regulation of Myt3 expression. Suppression of Myt3 was used to evaluate gene expression, insulin secretion and apoptosis in islets.
  
  
  RESULTS
  We show that Myt3 is the most abundant MYT family member in adult islets and that it is expressed in all the major endocrine cell types in the pancreas after E18.5. We demonstrate that Myt3 expression is directly regulated by Foxa2, Pdx1, and Neurod1, which are critical to normal β-cell development and function, and that Ngn3 induces Myt3 expression through alterations in the Myt3 promoter chromatin state. Further, we show that Myt3 expression is sensitive to both glucose and cytokine exposure. Of specific interest, suppressing Myt3 expression reduces insulin content and increases β-cell apoptosis, at least in part, due to reduced Pdx1, Mafa, Il-6, Bcl-xl, c-Iap2 and Igfr1 levels, while over-expression of Myt3 protects islets from cytokine induced apoptosis.
  
  
  CONCLUSIONS
  We have identified Myt3 as a novel transcriptional regulator with a critical role in β-cell survival. These data are an important step in clarifying the regulatory networks responsible for β-cell survival, and point to Myt3 as a potential therapeutic target for improving functional β-cell mass.
authors.affiliation: Child and Family Research Institute, British Columbia Children's Hospital and Sunny Hill Health Centre, Vancouver, British Columbia, Canada.
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Tennant
authors.forename: Ratib
authors.initials: R
authors.lastname: Islam
authors.forename: Marabeth M
authors.initials: MM
authors.lastname: Kramer
authors.forename: Yulia
authors.initials: Y
authors.lastname: Merkulova
authors.forename: Roger L
authors.initials: RL
authors.lastname: Kiang
authors.forename: Cheryl J
authors.initials: CJ
authors.lastname: Whiting
authors.forename: Brad G
authors.initials: BG
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D008156:Luciferases; D051379:Mice; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: D017931:DNA Primers; C581556:Myt3 protein, mouse; D034741:RNA, Small Interfering; D014157:Transcription Factors; D008156:Luciferases