Drosophila lipid droplets buffer the H2Av supply to protect early embryonic development

Abstract

Assembly of DNA into chromatin requires a delicate balancing act, as both dearth and excess of histones severely disrupt chromatin function [1-3]. In particular, cells need to carefully control histone stoichiometry: if different types of histones are incorporated into chromatin in an imbalanced manner, it can lead to altered gene expression, mitotic errors, and death [4-6]. Both the balance between individual core histones and the balance between core histones and histone variants are critical [5, 7]. Here, we find that in early Drosophila embryos, histone balance in the nuclei is regulated by lipid droplets, cytoplasmic fat-storage organelles [8]. Lipid droplets were previously known to function in long-term histone storage: newly laid embryos contain large amounts of excess histones generated during oogenesis [9], and the maternal supplies of core histone H2A and the histone variant H2Av are anchored to lipid droplets via the novel protein Jabba [3]. We find that in these embryos, synthesis of new H2A and H2Av is imbalanced, and that newly produced H2Av can be recruited to lipid droplets. When droplet sequestration is disrupted by mutating Jabba, embryos display an elevated H2Av/H2A ratio in nuclei as well as mitotic defects, reduced viability, and hypersensitivity to H2Av overexpression. We propose that in Drosophila embryos, lipid droplets serve as a histone buffer, not only storing maternal histones to support the early cell cycles but also transiently sequestering H2Av produced in excess and thus ensuring proper histone balance in the nucleus.