Valeria Levi

Martin Stortz, Camila Oses, Camila Vázquez Echegaray, Adali Pecci, Alejandra Guberman, Diego M. Presman and Valeria Levi

Facultad de Ciencias Exactas y Naturales-Universidad de Buenos Aires-Argentina

In the last few years, we have witnessed paradigmatic changes in our understanding of gene expression regulation. For example, the proposal of (and still deeply debated) liquid-liquid phase separation model to explain the heterogeneous distribution of nuclear processes suggests new layers of complexity in transcriptional regulation that moves farther and farther from the simple interaction of molecules with targets on DNA.

Here, we will discuss our studies on two, in principle, unrelated transcription factors (TFs). Steroid receptors (SRs) are ligand-dependent TFs relevant to key cellular processes in both physiology and pathology. On the other hand, SOX2 is a master TF of pluripotency of embryonic stem cells, and its dysregulation is also associated with various types of human cancers.

We show that the ectopic expression of SOX2 disrupts the formation of hormone-dependent intranuclear condensates of many steroid receptors (SRs), including those formed by the glucocorticoid receptor (GR). These effects on GR condensates do not require the intrinsically disordered N-terminal domain of the receptor and, surprisingly, neither relies on GR/SOX2 interactions. The pluripotency TF also alters the intranuclear dynamics and compartmentalization of the SR coactivator NCoA-2 and impairs GR/NCoA-2 interactions. Relevantly, SOX2 reduces GR’s binding to specific DNA targets and modulates its transcriptional activity.

Together, our results indicate that the nuclear organization of the receptor and its coregulators modulate the transcriptional program elicited by GR.