Cyclic AMP induces reversible EPAC1 condensates that regulate histone transcription

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Cyclic AMP (cAMP) is a crucial second messenger regulating diverse nuclear processes.
• While protein kinase A (PKA) mediates many cAMP effects, other effectors are implicated in nuclear functions.
• The nuclear role of Exchange Protein Activated by cAMP 1 (EPAC1) remains underexplored.

Purpose of the Study:

• To investigate the nuclear functions of EPAC1.
• To elucidate the mechanism of EPAC1-mediated nuclear regulation by cAMP.
• To identify novel cAMP signaling pathways in the nucleus.

Main Methods:

• Confocal microscopy to visualize EPAC1 localization and condensate formation.
• Biochemical assays to assess EPAC1-PKA independence.
• Chromatin immunoprecipitation and gene expression analysis to determine EPAC1's effect on histone gene transcription.

Main Results:

• EPAC1 translocates to the nucleus and forms reversible, cAMP-dependent biomolecular condensates.
• Condensate formation is mediated by EPAC1's intrinsically disordered N-terminal regions and is PKA-independent.
• Nuclear EPAC1 condensates localize to specific genomic loci on chromosome 6 near Histone Locus Bodies.
• EPAC1 condensates promote the transcription of a histone gene cluster.

Conclusions:

• EPAC1 acts as a novel nuclear effector of cAMP, forming spatial compartments.
• This PKA-independent pathway regulates gene transcription through condensate formation at specific loci.
• cAMP signaling contributes to nuclear organization and gene regulation via EPAC1 condensates.