Resetting the yeast epigenome with human nucleosomes

Abstract

Humans and yeast are separated by a billion years of evolution, yet their conserved core histones retain central roles in gene regulation. Here, we \"reset\" yeast to use core human nucleosomes in lieu of their own, an exceedingly rare event which initially took twenty days. The cells adapt, however, by acquiring suppressor mutations in cell-division genes, or by acquiring certain aneuploidy states. Robust growth was also restored by converting five histone residues back to their yeast counterparts. We reveal that humanized nucleosomes in yeast are positioned according to endogenous yeast DNA sequence and chromatin-remodeling network, as judged by a yeast-like nucleosome repeat length. However, human nucleosomes have higher DNA occupancy and reduce RNA content. Adaptation to new biological conditions presented a special challenge for these cells due to slower chromatin remodeling. This humanized yeast poses many fundamental new questions about the nature of chromatin and how it is linked to many cell processes, and provides a platform to study histone variants via yeast epigenome reprogramming.\n\nHighlights- Only 1 in 107 yeast survive with fully human nucleosomes, but they rapidly evolve\n- Nucleosome positioning and nucleosome repeat length is not influenced by histone type\n- Human nucleosomes remodel slowly and delay yeast environmental adaptation\n- Human core nucleosomes are more repressive and globally reduce transcription in yeast