Genetics and lability of intra-species epigenomic variation

Natural populations are known to differ not only in DNA but also in their chromatin-associated epigenetic marks. This diversity was reported in humans and model organisms, reflecting variations of cytosine methylation, histone acetylation, and global chromatin footprints and compaction. Understanding how this variability contributes to physiological differences is therefore highly exciting. However, this task remains challenging because epigenotypes can be of two different natures: they may be genetically encoded by DNA regulatory variation, or they may result from chromatin changes that occurred stochastically or in response to environmental conditions. Consequently, the history and heritability of epigenomic variations often escape interpretation, preventing the construction of a reliable framework for population epigenetics. We have performed a comprehensive analysis of environmentally induced resetting of yeast acetylation epi-polymorphisms, and we have generated a genome-by-epigenome map of their genetic control. This allowed us to tease apart ‘labile’ epi-polymorphisms that were not recovered after a transient environmental perturbation, from ‘persistent’ ones. We mapped hundreds of genetic loci underlying acetylation variation in cis or in trans at 2,418 nucleosomes. The architecture of this genetic control, its connection to the control of gene expression and its relevance to environmental persistence will be discussed. Our observations provide a basis for the development of population epigenetics, and they will help anticipate the possible long-term consequences of temporary treatments involving ‘epidrugs’