Gravitational Force—Induced 3D Chromosomal Conformational Changes Are Associated with Rapid Transcriptional Response in Human T Cells

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.

Microgravity-induced stress mechanisms in human stem cell-derived cardiomyocytes

“…However, it should be pointed out, that during the parabolic flight, the Jurkat T cells were exposed to 31 alternating hypergravity, microgravity, and hypergravity phases, each lasting 20–22 sec ( Acharya et al., 2019 ). In striking contrast, in the present study, CMs were continuously exposed exclusively to microgravity for 48 h. Therefore, due to fundamental experimental differences of the Hi-C data in our study and the study reported ( Vahlensieck et al., 2021 ) are not surprising. Nevertheless, it is evident that SMG also impacts large-scale chromosomal organization.…”

“…More recently, human Jurkat T cells were exposed to short-term gravitational changes in parabolic flight and suborbital ballistic rocket flight experiments ( Vahlensieck et al., 2021 ). Authors reported that smaller chromosomes (Chr 16–22 except for chr18) have higher intrachromosomal interactions compared to large chromosomes in altered gravity.…”

Changes in Higher-Order Chromosomal Structure of Klebsiella pneumoniae Under Simulated Microgravity

“…The spatial organization of the genome is essential for modulating gene regulation ( Kong and Zhang, 2019 ). In mammalian T cells, there is a non-random overlap between regions of chromosome structural changes and regions of DEGs in response to gravity changes ( Vahlensieck et al, 2021 ). In addition, our previous study found that under SMG, most DEGs of Vibrio natriegens were located in regions with changeable chromosome structures ( Yin et al, 2020 ).…”

“…A/B compartment analysis also revealed that chromosomes became more active. For eukaryotes, Vahlensieck et al (2021) reported that under normal gravity the nucleus is compressed by the force of gravity along the vertical axis, thus shortening it along the vertical axis and elongating it along the horizontal axis. In microgravity, these forces are no longer present, and the shape of the nucleus becomes more circular ( Vahlensieck et al, 2021 ).…”

“…For eukaryotes, Vahlensieck et al (2021) reported that under normal gravity the nucleus is compressed by the force of gravity along the vertical axis, thus shortening it along the vertical axis and elongating it along the horizontal axis. In microgravity, these forces are no longer present, and the shape of the nucleus becomes more circular ( Vahlensieck et al, 2021 ). In prokaryotes, similar change may occur in the microorganism chromatin, as suggested by our present and previous results.…”