Histone deacetylase HDA-4-mediated epigenetic regulation in space-flown C. elegans

Abstract

Epigenetic changes during long-term spaceflight are beginning to be studied by NASA’s twin astronauts and other model organisms. Here, we evaluate the epigenetic regulation of gene expression in space-flown C. elegans by comparing wild type and histone deacetylase (hda)-4 mutants. Expression levels of 39 genes were consistently upregulated in all four generations of adult hda-4 mutants grown under microgravity compared with artificial Earth-like gravity (1G). In contrast, in the wild type, microgravity-induced upregulation of these genes occurred a little. Among these genes, 11 contain the domain of unknown function 19 (DUF-19) and are located in a cluster on chromosome V. When compared with the 1G condition, histone H3 trimethylation at lysine 27 (H3K27me3) increased under microgravity in the DUF-19 containing genes T20D4.12 to 4.10 locus in wild-type adults. On the other hand, this increase was also observed in the hda-4 mutant, but the level was significantly reduced. The body length of wild-type adults decreased slightly but significantly when grown under microgravity. This decrease was even more pronounced with the hda-4 mutant. In ground-based experiments, one of the T20D4.11 overexpressing strains significantly reduced body length and also caused larval growth retardation and arrest. These results indicate that under microgravity, C. elegans activates histone deacetylase HDA-4 to suppress overregulation of several genes, including the DUF-19 family. In other words, the expression of certain genes, including negative regulators of growth and development, is epigenetically fine-tuned to adapt to the space microgravity.

Current Knowledge about the Impact of Microgravity on Gene Regulation

“…The gene expression in Caenorhabditis elegans was investigated in a series of experiments on the ISS: the results showed a downregulation of genes related to longevity [ 96 ] or metabolism and protein expression [ 89 ]. The most recent results indicate that the expression is partially regulated epigenetically: an overexpression of several genes was observed in histone deacetylase (had)-4 mutants as compared to wild types, indicating that in a wild-type organism, excessive expression of certain genes is epigenetically suppressed to the extent of a de facto downregulation, while in the had-4 mutant, the overexpression occurs unhampered ( Table 2 ) [ 90 ].…”

Gravitational and mechanical forces drive mitochondrial translation

“…To further extend our exploration from cell culture to the whole-body level, we used nematode samples flown in the ISS 16 . The L1 larvae were cultured under microgravity conditions for 4 d, while the control worms were incubated in a 1 × g centrifuge (Figure 1D).…”

“…Then, the samples were stored in a Minus Eighty degree Celsius Laboratory Freezer for ISS (MELFI) at −95°C. Samples were returned to the ground by SpaceX CRS-22 (SpX-22) in July 2021, maintaining their frozen status, and were stored at −80°C in the laboratory for ribosome profiling and RNA-seq.. Space-flown C. elegans samples prepared for earlier experiments ( 16 ) were used in this study.…”

Comparative Analysis of Muscle Atrophy During Spaceflight, Nutritional Deficiency and Disuse in the Nematode Caenorhabditis elegans

“…Previous studies have shown that C. elegans overall body length is smaller in space [ 20 , 26 ]. Thus, one possibility is that the smaller muscle area observed in space may be due to growth limitations in the space environment and overall smaller body size.…”