Abstract
The mechanisms underlying gravity perception in mammalian cells are unknown. We have recently discovered that the transcriptome of cells in the immune system, which is the most affected system during a spaceflight, responds rapidly and broadly to altered gravity. To pinpoint potential underlying mechanisms, we compared gene expression and three-dimensional (3D) chromosomal conformational changes in human Jurkat T cells during the short-term gravitational changes in parabolic flight and suborbital ballistic rocket flight experiments. We found that differential gene expression in gravity-responsive chromosomal regions, but not differentially regulated single genes, are highly conserved between different real altered gravity comparisons. These coupled gene expression effects in chromosomal regions could be explained by underlying chromatin structures. Based on a high-throughput chromatin conformation capture (Hi-C) analysis in altered gravity, we found that small chromosomes (chr16–22, with the exception of chr18) showed increased intra- and interchromosomal interactions in altered gravity, whereby large chromosomes showed decreased interactions. Finally, we detected a nonrandom overlap between Hi-C-identified chromosomal interacting regions and gravity-responsive chromosomal regions (GRCRs). We therefore demonstrate the first evidence that gravitational force-induced 3D chromosomal conformational changes are associated with rapid transcriptional response in human T cells. We propose a general model of cellular sensitivity to gravitational forces, where gravitational forces acting on the cellular membrane are rapidly and mechanically transduced through the cytoskeleton into the nucleus, moving chromosome territories to new conformation states and their genes into more expressive or repressive environments, finally resulting in region-specific differential gene expression.
Highlights
The gravitational force has been constant throughout the four billion years of Earth’s evolutionary history [1] and probably played a crucial role in the evolutionary development and adaptation of all terrestrial life [2,3]
The analyses focused on the identification and distribution of gravity-responsive chromosomal regions (GRCRs) of differentially expressed genes (DEGs) that show intense differential expression in one direction
To directly analyze the involvement of structural alterations of the chromatin caused by altered gravity on Differential gene expressions (DGEs), we further performed a high-throughput chromatin conformation capture (Hi-C) experiment on the 4th Swiss Parabolic Flight campaign to be able to correlate conformational changes with the localization of GRCRs
Summary
The gravitational force has been constant throughout the four billion years of Earth’s evolutionary history [1] and probably played a crucial role in the evolutionary development and adaptation of all terrestrial life [2,3]. Differential gene expressions (DGEs) in these cell lines were detectable after 20 s of altered gravity during a parabolic flight as well as after 75 s of hypergravity and 300 s of microgravity during a suborbital ballistic rocket flight. These alterations affect a major fraction of transcripts without significant overlaps and functional relations between the patterns of different time points [29,30,31,32,33,34,35]. Our data suggested a rapid coupling between the gravitational force and the transcriptome [34] after an initial trigger mechanism of less than 1 s reaction time [30]
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