Proopiomelanocortin gene expression and DNA methylation: implications for Cushing's syndrome and beyond

J Endocrinol. 2003 Jun;177(3):365-72. doi: 10.1677/joe.0.1770365.

Abstract

Proopiomelanocortin gene (POMC) is recognised as playing an important role in the regulation of the hypothalamo-pituitary-adrenal axis, adrenal development and obesity. POMC is activated in ACTH-dependent Cushing's syndrome. The syndrome may occur when the highly tIssue-specific 5' promoter of human POMC is activated in pituitary and non-pituitary sites. Whilst the factors involved in transcription in the corticotrophs of the anterior pituitary gland are becoming well delineated, the mechanism of activation in non-pituitary sites is not fully understood. This promoter is embedded within a defined CpG island, and, in contrast to somatically expressed CpG island promoters reported to date, is methylated in normal non-expressing tIssues, but is specifically unmethylated in expressing tIssues, tumours and the POMC-expressing DMS-79 small-cell lung cancer cell line. Methylation in vitro is sufficient for silencing of expression. In particular, methylation near the response element for the tIssue-specific POMC activator PTX1, diminishes POMC expression. Sites outside the PTX1 response element may be important for binding, and this may have implications for pituitary development. DMS-79 cells lack POMC-demethylating activity, implying that the methylation and expression patterns are likely to be set early or prior to neoplastic transformation, and that targeted de novo methylation might be a potential therapeutic strategy. It is conceivable that in POMC neurons of the hypothalamus the POMC promoter is subject to a variable density of methylation with clear implications for the signalling of satiety and obesity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • ACTH Syndrome, Ectopic / metabolism
  • Animals
  • CpG Islands
  • Cushing Syndrome / metabolism*
  • DNA Methylation*
  • Gene Expression Regulation / physiology*
  • Humans
  • Hypothalamus / metabolism
  • Neoplasms / metabolism
  • Obesity / metabolism
  • Pituitary Gland / metabolism*
  • Pro-Opiomelanocortin / genetics*
  • Promoter Regions, Genetic*
  • Response Elements

Substances

  • Pro-Opiomelanocortin