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bioRxiv · 10.1101/2025.09.01.673508

Mechanistic dissection of GRHL2 and PR transcriptional co-regulation in breast cells

Aarts, M. T.·Nordin, A.·Cantu, C.·van Boxtel, A. L.·van Amerongen, R.
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Abstract

Gene expression is controlled by complex transcriptional networks in which transcription factors and their cognate enhancer elements integrate developmental and environmental cues. The progesterone receptor (PR), a hormone-activated transcription factor, is essential for breast development and physiology, yet how it engages with the chromatin and lineage-specific cofactors remains unclear. Using an unbiased approach, we identify the epithelial transcription factor grainyhead-like 2 (GRHL2) as a key co-regulator of PR activity in hormone responsive breast cancer cells. We show that GRHL2 interacts with PR in a progesterone-independent manner. Upon progesterone stimulation, GRHL2 and PR are both recruited to distal enhancer elements of target genes. Furthermore, GRHL2- and PR-bound elements connect spatially through chromatin looping to regulate shared targets. These findings uncover a previously unrecognized mechanism by which GRHL2 and PR coordinate gene regulation through both chromatin binding and 3D genome architecture modification, positioning GRHL2 as a crucial modulator of steroid hormone receptor function.

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Aarts, M. T., Nordin, A., Cantu, C., van Boxtel, A. L., van Amerongen, R.. 2025-09-05. Mechanistic dissection of GRHL2 and PR transcriptional co-regulation in breast cells. https://doi.org/10.1101/2025.09.01.673508

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