The cAMP signaling pathway regulates Epe1 protein levels and heterochromatin assembly

Author summaryGenomic DNA is folded with histones into chromatin and posttranslational modifications on histones separate chromatin into active euchromatin and repressive heterochromatin. These chromatin domains often change in response to environmental cues, such as nutrient levels. How environmental changes affect histone modifications is not well understood. Here, we found that in fission yeast, the cAMP signaling pathway is required for the function of Epe1, an enzyme that removes histone modifications associated with heterochromatin. Moreover, we found that active cAMP signaling ensures the efficient translation of epe1(+) mRNA and therefore maintains high Epe1 protein levels. Finally, we show that changing glucose levels, which modulate cAMP signaling, also affect heterochromatin in a way consistent with cAMP signaling-mediated Epe1 protein level changes. As histone-modifying enzymes often require cofactors that are metabolic intermediates, previous studies on the impact of nutrient levels on chromatin states have mainly focused on metabolites. Our results suggest that nutrient-sensing signaling pathways also regulate histone-modifying enzymes in response to nutritional conditions. The epigenetic landscape of a cell frequently changes in response to fluctuations in nutrient levels, but the mechanistic link is not well understood. In fission yeast, the JmjC domain protein Epe1 is critical for maintaining the heterochromatin landscape. While loss of Epe1 results in heterochromatin expansion, overexpression of Epe1 leads to defective heterochromatin. Through a genetic screen, we found that mutations in genes of the cAMP signaling pathway suppress the heterochromatin defects associated with Epe1 overexpression. We further demonstrated that the activation of Pka1, the downstream effector of cAMP signaling, is required for the efficient translation of epe1(+) mRNA to maintain Epe1 overexpression. Moreover, inactivation of the cAMP-signaling pathway, either through genetic mutations or glucose deprivation, leads to the reduction of endogenous Epe1 and corresponding heterochromatin changes. These results reveal the mechanism by which the cAMP signaling pathway regulates heterochromatin landscape in fission yeast.