Proopiomelanocortin gene expression and DNA methylation: implications for Cushing's syndrome and beyond.
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.
Newell-Price
J
J
Division of Clinical Sciences, Sheffield University, Northern General Hospital, Herries Road, Sheffield S5 7AU, UK. j.newellprice@sheffield.ac.uk
D000182:ACTH Syndrome, Ectopic / Q000378:metabolism; D000818:Animals; D018899:CpG Islands; D003480:Cushing Syndrome / Q000378:metabolism*; D019175:DNA Methylation; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D010902:Pituitary Gland / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D011401:Promoter Regions, Genetic; D020218:Response Elements
D011333:Pro-Opiomelanocortin