Nucleophosmin 1 cooperates with the methyltransferase DOT1L to regulate H3K79me2 levels and DNA satellites expression at peri-nucleolar heterochromatin

Abstract

Abstract Background The histone methyltransferase DOT1L catalyzes methylation of H3K79 and it is highly conserved in mammals. DOT1L plays a functional role in several biological processes including cell cycle regulation, DNA repair, RNA splicing and gene expression, suggesting a complex role in chromatin organization and regulation. Such a remarkable range of functions performed by DOT1L can be the result, at least partially, of its interaction with a plethora of proteins and presence in different complexes. Results Here, we characterized the cooperation of DOT1L with the nucleolar protein NPM1 and the impact of both proteins on peri-nucleolar heterochromatin activity. We show that i) DOT1L interacts preferentially with monomeric NPM1 in the nucleus; ii) DOT1L acts in concert with NPM1 to maintain each other’s protein homeostasis; iii) NPM1 depletion results in H3K79me2 upregulation at chromatin remodeling genes but does not affect their expression; iv) DOT1L and NPM1 preserved DNA satellite expression at peri-nucleolar heterochromatin via epigenetic mechanisms dependent on H3K27me3. Conclusions Our findings give insights into molecular mechanisms employed by DOT1L and NPM1 to regulate heterochromatin activities around the nucleoli and shed light on one aspect of the complex role of both proteins in chromatin dynamics.