Genetic Modifiers of Chromatin Acetylation Antagonize the Reprogramming of Epi-Polymorphisms

Anne-Laure Abraham,Lars M Steinmetz,Gaël Yvert,Jean-Baptiste Veyrieras,Muniyandi Nagarajan,Hélène Bottin

doi:10.1371/journal.pgen.1002958

Abstract

Natural populations are known to differ not only in DNA but also in their chromatin-associated epigenetic marks. When such inter-individual epigenomic differences (or “epi-polymorphisms”) are observed, their stability is usually not known: they may or may not be reprogrammed over time or upon environmental changes. In addition, their origin may be purely epigenetic, or they may result from regulatory variation encoded in the DNA. Studying epi-polymorphisms requires, therefore, an assessment of their nature and stability. Here we estimate the stability of yeast epi-polymorphisms of chromatin acetylation, and we provide a genome-by-epigenome map of their genetic control. A transient epi-drug treatment was able to reprogram acetylation variation at more than one thousand nucleosomes, whereas a similar amount of variation persisted, distinguishing “labile” from “persistent” epi-polymorphisms. Hundreds of genetic loci underlied acetylation variation at 2,418 nucleosomes either locally (in cis) or distantly (in trans), and this genetic control overlapped only partially with the genetic control of gene expression. Trans-acting regulators were not necessarily associated with genes coding for chromatin modifying enzymes. Strikingly, “labile” and “persistent” epi-polymorphisms were associated with poor and strong genetic control, respectively, showing that genetic modifiers contribute to persistence. These results estimate the amount of natural epigenomic variation that can be lost after transient environmental exposures, and they reveal the complex genetic architecture of the DNA–encoded determinism of chromatin epi-polymorphisms. Our observations provide a basis for the development of population epigenetics.

Highlights

Recent studies have shown that individuals largely differ in their epigenomic chromatin signatures
DNase-seq profiles of cell-lines from human families revealed,10,000 sites that were polymorphic in their chromatin signature [10] and it is likely that a significant fraction of them is not associated with DNA methylation differences but with other regulatory hallmarks
Using a chemical perturbation of yeast cells as an experimental model system, we found that acetylation variation was persistent at some nucleosomes and labile at other nucleosomes

Summary

Introduction

Recent studies have shown that individuals largely differ in their epigenomic chromatin signatures. Numerous inter-individual differences of DNA methylation were reported [3,4,5,6] and, importantly, the methylomes of monozygotic twins were shown to diverge during their lifetime [7]. Measuring this diversity at a genome-wide scale extended what had been observed earlier at individual loci in mice, where the level of transgene methylation was shown to strongly vary between laboratory strains [8,9]. Histone acetylation profiles varies, as we previously described in a comparison of two unrelated wild strains of S. cerevisiae [12]

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Discussion

Conclusion