How Estrogen Receptors Activate Genes Visualized

Scientists at Nano Life Science Institute (WPI-NanoLSI), Kanazawa University have captured real-time footage showing how a key hormone receptor activates genes, offering a clearer view into one of the most fundamental processes in biology.

Using high-speed atomic force microscopy (HS-AFM), Richard Wong and colleagues at Kanazawa University directly visualized how the estrogen receptor alpha (ERα) binds to DNA and switches on genes in response to the hormone estrogen. Their findings, published in ACS Nano, reveal new molecular details of hormone signaling, with important implications for diseases like breast cancer.

Estrogen receptors play a critical role in controlling gene activity in many tissues. When estrogen binds to ERα, the protein changes shape, forms a dimer (a molecular pair), and attaches to specific regions of DNA called estrogen response elements (EREs). Although the importance of this process has been known for decades, it had never before been observed unfolding at the single-molecule level in real time.

To capture this, the researchers used HS-AFM to scan individual ERα molecules interacting with DNA. They compared the behavior of ERα with and without estrogen present. Their experiments showed that ERα could bind to DNA without estrogen but did so less precisely and less stably. When estrogen was present, ERα molecules dimerized more efficiently and exhibited targeted, stable binding to ERE sequences.

“Our study shows that estrogen acts like a molecular matchmaker,” says Richard Wong. “It not only triggers ERα to find the right DNA sequence but also stabilizes its grip, ensuring accurate gene activation.”

Based on these observations, the team proposed a new ‘Ligand-Induced Dimerization’ (LID) model explaining how hormones fine-tune the dynamic behavior of receptors at the DNA level.

This work provides direct visual evidence of how molecular signals from hormones lead to precise gene control — a fundamental advance that could guide new strategies for treating hormone-driven diseases.

Reference: Nishide G, Ishibashi T, Lim K, et al. Zooming into gene activation: estrogen receptor α dimerization and DNA binding visualized by high-speed atomic force microscopy. ACS Nano. 2025;19(16):15395-15410. doi: 10.1021/acsnano.4c14943

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