The Paramount Role of Drosophila melanogaster in the Study of Epigenetics: From Simple Phenotypes to Molecular Dissection and Higher-Order Genome Organization

SIMPLE SUMMARY: Since its adoption as a model organism more than a hundred years ago, the fruit fly Drosophila melanogaster has led to major discoveries in biology, notably in epigenetics. Epigenetics studies the changes in gene function inherited through mitosis or meiosis that are not due to modifications in the DNA sequence. The first discoveries in epigenetics emerged from analyses of the perturbations of simple phenotypes such as the bristle position or cuticle pigmentation. Identification of the mutated genes led to the discovery of major chromatin regulators, which were found to be conserved in other insects, and unexpectedly, in all metazoans. Many of them deposit post-translational modifications on histones, the proteins around which the DNA is wrapped. Others are chromatin remodeling complexes that move, eject, or exchange nucleosomes. We review here the role of D. melanogaster research in three important epigenetic fields: The formation of heterochromatin, the repression of mobile DNA elements by small RNAs, and the regulation of gene expression by the antagonistic Polycomb and Trithorax complexes. We then review how genetic tools available in D. melanogaster have allowed us to examine the role of histone marks and led to more global discoveries on chromatin organization. Lastly, we discuss the impact of varying environmental conditions on epigenetic regulation. ABSTRACT: Drosophila melanogaster has played a paramount role in epigenetics, the study of changes in gene function inherited through mitosis or meiosis that are not due to changes in the DNA sequence. By analyzing simple phenotypes, such as the bristle position or cuticle pigmentation, as read-outs of regulatory processes, the identification of mutated genes led to the discovery of major chromatin regulators. These are often conserved in distantly related organisms such as vertebrates or even plants. Many of them deposit, recognize, or erase post-translational modifications on histones (histone marks). Others are members of chromatin remodeling complexes that move, eject, or exchange nucleosomes. We review the role of D. melanogaster research in three epigenetic fields: Heterochromatin formation and maintenance, the repression of transposable elements by piRNAs, and the regulation of gene expression by the antagonistic Polycomb and Trithorax complexes. We then describe how genetic tools available in D. melanogaster allowed to examine the role of histone marks and show that some histone marks are dispensable for gene regulation, whereas others play essential roles. Next, we describe how D. melanogaster has been particularly important in defining chromatin types, higher-order chromatin structures, and their dynamic changes during development. Lastly, we discuss the role of epigenetics in a changing environment.