Steroid receptors can facilitate the binding of the pioneer factor FoxA1 in breast cancer cell lines through a dynamic assisted loading (DynALoad) mechanism

FARE Award Winner

Authors

• EE Swinstead
• TB Miranda
• V Paakinaho
• DM Presman
• S Baek
• M Hawkins
• T Karpova
• D Ball
• L Grøntved
• GL Hager

Abstract

The steroid receptors (SRs), estrogen receptor (ER) and glucocorticoid receptor (GR) in addition with FoxA1 all play an important role in breast cancer development however these interactions are not well understood. FoxA1 has been implicated in ER binding patterns serving as a pioneer factor; however, the effects of ER on the function of FoxA1 has been controversial. Classically it has been proposed that FoxA1 has a slow residence time on DNA allowing chromatin to remain open permitting access of SRs to binding sites. Conversely, it has recently been identified that SRs can alter the binding landscape of other SRs facilitating selective access to the chromatin by a mechanism termed dynamic assisted loading (DynALoad). To determine if the DynALoad phenomenon extends to FoxA1 we characterised GR, ER, and FoxA1 crosstalk in three estrogenic breast cancer cell lines. Genome-wide analysis of FoxA1 binding upon hormone treatment shows that both activated ER and GR can recruit FoxA1 to specific binding sites associated with an increase in chromatin accessibility. This indicates chromatin reorganization upon activation of ER and GR and recruitment of FoxA1 binding through a DynALoad mechanism. Most importantly, there is a lack of a FoxA1 DNase footprint in these cells suggesting the binding pattern is highly dynamic with a short DNA residence time. These results suggest that many TFs in a given cell have the potential to affect the binding landscape of other TFs, depending on the chromatin context shifting our classical understanding of pioneer factors in breast cancer.

Scientific Focus Area: Molecular Biology and Biochemistry

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