The second messenger cyclic AMP (cAMP) regulates numerous nuclear processes, including transcription, pre-mRNA splicing, and mitosis.
Although most of these functions have been attributed to protein kinase A (PKA), growing evidence suggests that not all cAMP-dependent nuclear effects are mediated by this kinase, implying the involvement of additional effectors.
In this study, we explored the nuclear roles of the Exchange Protein Directly Activated by cAMP 1 (EPAC1). We found that EPAC1 translocates into the nucleus, where it forms reversible biomolecular condensates in response to cAMP. This phenomenon depends on intrinsically disordered regions located at its amino terminus and occurs independently of PKA activity.
Finally, we demonstrate that nuclear EPAC1 condensates assemble at genomic loci on chromosome 6 near histone locus bodies and promote the transcription of a histone gene cluster. Collectively, our findings reveal an unexpected mechanism through which cAMP contributes to nuclear spatial compartmentalization and promotes the transcription of specific genes.
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