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Two Distinctive POMC Promoters Modify Gene Expression in Cushing Disease
Takako Araki1,2, Yukiko Tone3, Masaaki Yamamoto1
1Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
The Journal of Clinical Endocrinology and Metabolism
|June 1, 2021
Summary
Scientists discovered a new regulatory region in the proopiomelanocortin (POMC) gene that acts as a second promoter. Its methylation status in pituitary tumors influences adrenocorticotropin (ACTH) production, offering potential therapeutic targets.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Pituitary corticotroph adenoma adrenocorticotropin (ACTH) production mechanisms are not fully understood.
- Circulating ACTH levels correlate with adenoma phenotype and clinical outcomes.
Purpose of the Study:
- To investigate additional regulatory mechanisms of POMC gene transcription and ACTH production.
- To characterize the 5' ends of POMC gene transcripts.
Main Methods:
- Examined 11 normal human pituitary tissues, 32 ACTH-secreting tumors, and 6 silent corticotroph adenomas (SCAs).
- Analyzed POMC gene transcripts and promoter methylation status.
Main Results:
- Identified a novel second POMC promoter and enhancer region.
- Demonstrated CREB binding and regulation of the second promoter.
- Found differential methylation patterns of the second promoter in SCAs, normal pituitary, and ACTH-secreting tumors.
- Observed correlation between second promoter demethylation and Cushing disease phenotypes.
Conclusions:
- A second POMC promoter, regulated by methylation, was identified in ACTH-secreting pituitary tumors.
- Findings provide insights into hypothalamic-pituitary-adrenal axis regulation.
- The second POMC promoter may serve as a therapeutic target for excess ACTH production.
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