Final Report Summary - CHROMATINMODWEB (Functional and regulatory protein networks of chromatin modifying enzymes)
Chromatin modifying enzymes and their associated histone modifications constitute one of the main epigenetic mechanism through which cells regulate gene transcription. Deregulation of this epigenetic mechanism can lead to diseases such as cancer and therefore, these enzymes are currently exploited as drug targets in cancer therapy. During this project we unveiled the cellular function and molecular mechanisms employed by an important but previously uncharacterized histone modifying enzyme known as Nat4. This enzyme specifically catalyzes histone N-alpha-terminal acetylation, an abundant and evolutionarily conserved modification. In particular, we have shown that in yeast cells N-terminal acetylation of histone H4 (N-acH4) regulates the expression of ribosomal RNA genes by inhibiting the deposition of an adjacent repressive histone modification (H4R3me2a). Furthermore, the activity of Nat4 towards histone H4 at the yeast rDNA region is reduced during nutrient deprivation suggesting that Nat4 and N-acH4 act as epigenetic sensors for certain extracellular signals. Consistent with this, we have shown that Nat4 and its associate N-acH4 modification control the longevity effect mediated by calorie restriction. Upon glucose limitation, Nat4 is depleted and N-acH4 removed from chromatin in order to allow the induction of stress-response genes which are then responsible for increasing cellular stress-resistance and lifespan. Finally, we demonstrated that the function of Nat4 is conserved in humans since its human counterpart Naa40 mediates N-acH4 to control gene expression. Most importantly, depletion of human Naa40 in colon carcinoma cells induces robust cell-death through a mitochondrial apoptotic pathway. These latter findings implicate Naa40 and histone H4 N-terminal acetylation in human carcinogenesis and propose that pharmacological inhibition of this epigenetic enzyme should be explored as a therapeutic strategy.