Changes in Nuclear Shape and Gene Expression in Response to Simulated Microgravity Are LINC Complex-Dependent

Neelam, Srujana; Richardson, Brian; Barker, Richard; Udave, Ceasar; Gilroy, Simon; Cameron, Mark J.; Levine, Howard G.; Zhang, Ye

doi:10.3390/ijms21186762

Cited by 20 publications

(21 citation statements)

References 67 publications

(99 reference statements)

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“…Following these rapid and transient effects, further gene-specific regulatory effects, such as transcription factors, may become the dominant influence in the expression patterns, leading to the seemingly uncorrelated behaviors of different altered gravity platforms on the single-gene level (Figure 9b) [31]. We therefore confirmed previous explanations on how gravitational forces influence early gene regulation in the cell, involving alterations in cell shape and mechanical stress [111] that propagates from the cellular membrane via the cytoskeleton to organelles including the nucleus [112,113]. We also proposed that the rapid and specific gene expression response to the altered gravitational force is encoded in the gene position within the chromosome architecture.…”

Section: Discussionsupporting

confidence: 84%

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

Vahlensieck

Thiel

Zhang

et al. 2021

IJMS

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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.

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Section: Discussionsupporting

confidence: 84%

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

Vahlensieck

Thiel

Zhang

et al. 2021

IJMS

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“…The result is a positive loop, where an increased YAP nuclear-cytoplasmic ratio promotes more focal adhesions, leading to more YAP nuclear localisation [ 55 ]. An example of applying mechanobiology to µ g research showed that the changes in nuclear shape and gene expression observed in s-µ g are dependent on the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex [ 56 ].…”

Section: General Effects Of Microgravitymentioning

confidence: 99%

Cancer Studies under Space Conditions: Finding Answers Abroad

et al. 2021

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In this review article, we discuss the current state of knowledge in cancer research under real and simulated microgravity conditions and point out further research directions in this field. Outer space is an extremely hostile environment for human life, with radiation, microgravity, and vacuum posing significant hazards. Although the risk for cancer in astronauts is not clear, microgravity plays a thought-provoking role in the carcinogenesis of normal and cancer cells, causing such effects as multicellular spheroid formation, cytoskeleton rearrangement, alteration of gene expression and protein synthesis, and apoptosis. Furthermore, deleterious effects of radiation on cells seem to be accentuated under microgravity. Ground-based facilities have been used to study microgravity effects in addition to laborious experiments during parabolic flights or on space stations. Some potential ‘gravisensors’ have already been detected, and further identification of these mechanisms of mechanosensitivity could open up ways for therapeutic influence on cancer growth and apoptosis. These novel findings may help to find new effective cancer treatments and to provide health protection for humans on future long-term spaceflights and exploration of outer space.

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“…Chromatin condensation and margination associated with expression changes for genes in the Bcl2-apoptosis pathway and for proteins in the PI3K/Akt pathway have been observed in human endothelial cells incubated for 72 h in simulated microgravity [ 110 ]. Moreover, genes whose expression is dependent on the linker of the nucleoskeleton and cytoskeleton (LINC) complex, connecting chromatin with the nuclear surface, were altered in human breast epithelial cells cultured under simulated microgravity [ 111 ].…”

Section: Genomic Alterations In Human Cells Cultured In Simulated Space Conditionsmentioning

confidence: 99%

Genomic Changes Driven by Radiation-Induced DNA Damage and Microgravity in Human Cells

Beheshti

McDonald

Hada

et al. 2021

IJMS

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The space environment consists of a complex mixture of different types of ionizing radiation and altered gravity that represents a threat to humans during space missions. In particular, individual radiation sensitivity is strictly related to the risk of space radiation carcinogenesis. Therefore, in view of future missions to the Moon and Mars, there is an urgent need to estimate as accurately as possible the individual risk from space exposure to improve the safety of space exploration. In this review, we survey the combined effects from the two main physical components of the space environment, ionizing radiation and microgravity, to alter the genetics and epigenetics of human cells, considering both real and simulated space conditions. Data collected from studies on human cells are discussed for their potential use to estimate individual radiation carcinogenesis risk from space exposure.

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Changes in Nuclear Shape and Gene Expression in Response to Simulated Microgravity Are LINC Complex-Dependent

Cited by 20 publications

References 67 publications

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

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

Cancer Studies under Space Conditions: Finding Answers Abroad

Genomic Changes Driven by Radiation-Induced DNA Damage and Microgravity in Human Cells

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