DNA Methylation Is Essential in Regulating Cortisol Production, Study Shows

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by Alice Melao |

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USP8 and Cushing's

Excess cortisol in cortisol-producing adenomas may be caused by a lack of chemical modifications in a gene involved in cortisol synthesis, new research found.

The study shows that DNA methylation, a type of modification in the DNA whose function is to reduce protein expression, in the aldosterone synthase gene is significantly lower in cortisol-producing adenomas compared to normal adrenal tissue, providing a rationale for high cortisol production in these adenomas.

The study, “Cortisol overproduction results from DNA methylation of CYP11B1 in hypercortisolemia,” was published in the journal Scientific Reports.

Hypercortisolemia, a condition characterized by prolonged and excess cortisol production, is associated with several diseases, including hypertension and diabetes. It is also linked to higher mortality rates.

The condition results from a variety of disorders, including cortisol-producing adenoma (CPA), excess adrenocorticotropic hormone (ACTH) produced by the pituitary gland (Cushing’s disease), or by benign tumors producing ACTH (ectopic Cushing’s syndrome), among others.

Cortisol synthesis is mainly regulated by a signaling pathway activated by the ACTH. One of the proteins involved in this signaling is the aldosterone synthase, or CYP11B1. Studies have reported that CPA patients sometimes carry mutations that increase the levels of CYP11B1 and promote the activation of this pathway, leading to an excessive production of cortisol. However, it is still unclear how these mutations increase CYP11B1 levels.

To shed light on this, a research team at the Kanazawa University Hospital in Japan evaluated if CYP11B1 gene levels were regulated by a process called DNA methylation.

DNA methylation is a mechanism that cells have to regulate gene expression. When genes are methylated, the machinery that reads the DNA to produce proteins is unable to do so. But if a gene is not methylated, the machinery can normally bind and read its sequence, increasing its protein levels.

The team compared the methylation status of CYP11B1 between cortisol-producing adenomas (CPA), non-functioning adrenal tumors (NFT), or those that do not produce excess hormones, and normal adrenal samples.

They found that the DNA sequence of CYP11B1 was less methylated in CPA samples than in the others.

Overall, these findings suggest that CYP11B1 levels can be regulated by its gene methylation status, and that this cellular mechanism has great implications for excessive cortisol production.

“Methylation analysis of [genes] of key enzymes appears to play a significant role in the expression of the enzymes and physiological regulation of hormone biosynthesis,” the researchers wrote.

“Therefore, DNA methylation at the [genes] might make a significant contribution to not only the [development] of hormone producing adenomas, such as hypercortisolemia and CPA, but also the hormonal synthesis mechanism of the normal adrenal gland,” they added.