Abstract: In eukaryotic cells, transport of macromolecules across the nuclear envelope is an essential process that ensures rapid exchange of cellular components, including protein and RNA molecules. Chromatin regulators involved in epigenetic control are among the molecules exported across the nuclear envelope, but the significance of this nucleo‐cytoplasmic trafficking is not well understood. Here, we use a forward screen to isolate XPO1A (a nuclear export receptor in Arabidopsis) as an anti‐silencing factor that protects transgenes from transcriptional silencing. Loss‐of‐function of XPO1A leads to locus‐specific DNA hypermethylation at transgene promoters and some endogenous loci. We found that XPO1A directly interacts with histone deacetylase HDA6 in vivo and that the xpo1a mutation causes increased nuclear retention of HDA6 protein and results in reduced histone acetylation and enhanced transgene silencing. Our results reveal a new mechanism of epigenetic regulation through the modulation of XPO1A‐dependent nucleo‐cytoplasm partitioning of a chromatin regulator.