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

• Published in: Journal of endocrinology Vol. 177; no. 3; pp. 365 - 372
• Main Author: Newell-Price, J
• Format: Journal Article
• Language: English
• Published: England BioScientifica 01.06.2003
• Subjects: 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
• ISSN: 0022-0795; 1479-6805
• DOI: 10.1677/joe.0.1770365

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.