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Sequestration to lipid droplets promotes histone availability by preventing turnover of excess histones.

ABSTRACT: Because both dearth and overabundance of histones result in cellular defects, histone synthesis and demand are typically tightly coupled. In Drosophila embryos, histones H2B, H2A and H2Av accumulate on lipid droplets (LDs), which are cytoplasmic fat storage organelles. Without LD binding, maternally provided H2B, H2A and H2Av are absent; however, how LDs ensure histone storage is unclear. Using quantitative imaging, we uncover when during oogenesis these histones accumulate, and which step of accumulation is LD dependent. LDs originate in nurse cells (NCs) and are transported to the oocyte. Although H2Av accumulates on LDs in NCs, the majority of the final H2Av pool is synthesized in oocytes. LDs promote intercellular transport of the histone anchor Jabba and thus its presence in the ooplasm. Ooplasmic Jabba then prevents H2Av degradation, safeguarding the H2Av stockpile. Our findings provide insight into the mechanism for establishing histone stores during Drosophila oogenesis and shed light on the function of LDs as protein-sequestration sites.

SUBMITTER: Stephenson RA

PROVIDER: S-EPMC8380457 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Sequestration to lipid droplets promotes histone availability by preventing turnover of excess histones.

Stephenson Roxan A RA Thomalla Jonathon M JM Chen Lili L Kolkhof Petra P White Roger P RP Beller Mathias M Welte Michael A MA

Development (Cambridge, England) 20210806 15

Because both dearth and overabundance of histones result in cellular defects, histone synthesis and demand are typically tightly coupled. In Drosophila embryos, histones H2B, H2A and H2Av accumulate on lipid droplets (LDs), which are cytoplasmic fat storage organelles. Without LD binding, maternally provided H2B, H2A and H2Av are absent; however, how LDs ensure histone storage is unclear. Using quantitative imaging, we uncover when during oogenesis these histones accumulate, and which step of ac ...[more]

PMID: 34355743

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Project description:BACKGROUND:Alcohol consumption during pregnancy is a significant public health problem and can result in a continuum of adverse outcomes to the fetus known as fetal alcohol spectrum disorders (FASD). Subjects with FASD show significant neurological deficits, ranging from microencephaly, neurobehavioral, and mental health problems to poor social adjustment and stress tolerance. Neurons are particularly sensitive to alcohol exposure. The neurotoxic action of alcohol, i.e., through ROS production, induces DNA damage and neuronal cell death by apoptosis. In addition, epigenetics, including DNA methylation, histone posttranslational modifications (PTMs), and non-coding RNA, play an important role in the neuropathology of FASD. However, little is known about the temporal dynamics and kinetics of histones and their PTMs in FASD. RESULTS:We examined the effects of postnatal alcohol exposure (PAE), an animal model of human third-trimester equivalent, on the kinetics of various histone proteins in two distinct brain regions, the frontal cortex, and the hypothalamus, using in vivo 2H2O-labeling combined with mass spectrometry-based proteomics. We show that histones have long half-lives that are in the order of days. We also show that H3.3 and H2Az histone variants have faster turnovers than canonical histones and that acetylated histones, in general, have a faster turnover than unmodified and methylated histones. Our work is the first to show that PAE induces a differential reduction in turnover rates of histones in both brain regions studied. These alterations in histone turnover were associated with increased DNA damage and decreased cell proliferation in postnatal rat brain. CONCLUSION:Alterations in histone turnover might interfere with histone deposition and chromatin stability, resulting in deregulated cell-specific gene expression and therefore contribute to the development of the neurological disorders associated with FASD. Using in vivo 2H2O-labeling and mass spectrometry-based proteomics might help in the understanding of histone turnover following alcohol exposure and could be of great importance in enabling researchers to identify novel targets and/or biomarkers for the prevention and management of fetal alcohol spectrum disorders.

Dataset Information

Sequestration to lipid droplets promotes histone availability by preventing turnover of excess histones.

Publications

Sequestration to lipid droplets promotes histone availability by preventing turnover of excess histones.

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