NEW PERSPECTIVES ON ENDOCRINE SIGNALLING 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 ex-pression. 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