Drosophila Lipid Droplets Buffer the H2Av Supply to Protect Early Embryonic Development

Abstract

Summary Assembly of DNA into chromatin requires a delicate balancing act, as both dearth and excess of histones severely disrupts 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 between core histones and histone variants is 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.

Lipid droplet autophagy during energy mobilization lipid homeostasis and protein quality control

“…Defects in this process results in toxic accumulation of histones, which leads to mitotic error and apoptosis (76, 77). LDs also sequester misfolded cytosolic proteins and prevent them from forming toxic aggregates under several pathological states and conditions (78, 79).…”

As the fat flies: The dynamic lipid droplets of Drosophila embryos

“…Using both forward and reverse genetic strategies, a number of proteins have been confirmed to play roles in lipid-droplet biology in embryos, in particular for droplet motion [56, 57, 76, 77, 83-87, 105, 109, 110] and for protein sequestration [16, 75]. …”

“…4E). Although new translation of histones was initially thought to make little contribution before cycle 14 [158, 165], histone levels do indeed rise after fertilization [75] and lack of zygotic transcription of histones has been linked to increased risk of DNA damage [166]. In Jabba mutant embryos, new synthesis of H2A/H2B/H2Av proteins is able to compensate for the lack of the maternal histone deposit so that by 3.5 hrs of development, they have caught up to wild-type levels [16].…”

“…Certain histones are abundant on lipid droplets, and they can be transferred to nuclei and contribute to proper chromatin assembly [15, 16, 75] (Fig. 4B,D,E).…”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…Droplets of Drosophila early embryos store certain histones through an interaction with the droplet surface protein Jabba. In the absence of Jabba, the histones are degraded (Cermelli et al, 2006;Li et al, 2012Li et al, , 2014, suggesting that lipid droplets not only store lipid precursors but also can supply histones for rapid chromatin remodeling.…”