Oestrogen shapes the brain from youth to old age

Researchers studied how oestrogen, acting through a specific receptor (oestrogen receptor alpha), regulates gene activity within a TAD. A TAD (topologically associating domain) is a stretch of DNA that folds as a unit and activates or suppresses its own genes from within. The findings were published in eLife.

The study shows that when oestrogen activates an enhancer (a DNA switch that turns genes on), that does not only affect the target gene. It simultaneously suppresses neighbouring genes within the same TAD, but only after the oestrogen signal fades. There is, in effect, a molecular relay: one gene is switched on first, then another.

What does this have to do with brain aging?

Oestrogen is active in the brain throughout the entire lifespan. During puberty it guides the maturation of brain structures. In middle age and beyond, as oestrogen levels fall after menopause, gene expression patterns in brain cells also change. Earlier research has linked low post-menopausal oestrogen levels to a higher risk of cognitive decline and Alzheimer’s in women. This research shows that oestrogen regulates gene activity in a precise and time-dependent manner, suggesting that disruptions to it can have effects at any point in life.

Implications for hormone therapy remain uncertain

The mechanism described here was studied in breast cancer cell lines, not in brain cells or humans. The translation to clinical recommendations about hormone therapy is therefore preliminary. But it does offer a molecular framework for understanding why the timing of hormone therapy after menopause may matter for brain health. The researchers suggest that the behaviour of DNA domains partly determines which genes are activated when, and that oestrogen levels influence that timing.

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