Abstract
The gravitational force has been constant throughout Earth’s evolutionary history. Since the cell nucleus is subjected to permanent forces induced by Earth’s gravity, we addressed the question, if gene expression homeostasis is constantly shaped by the gravitational force on Earth. We therefore investigated the transcriptome in force-free conditions of microgravity, determined the time frame of initial gravitational force-transduction to the transcriptome and assessed the role of cation channels. We combined a parabolic flight experiment campaign with a suborbital ballistic rocket experiment employing the human myelomonocytic cell line U937 and analyzed the whole gene transcription by microarray, using rigorous controls for exclusion of effects not related to gravitational force and cross-validation through two fully independent research campaigns. Experiments with the wide range ion channel inhibitor SKF-96365 in combination with whole transcriptome analysis were conducted to study the functional role of ion channels in the transduction of gravitational forces at an integrative level. We detected profound alterations in the transcriptome already after 20 s of microgravity or hypergravity. In microgravity, 99.43% of all initially altered transcripts adapted after 5 min. In hypergravity, 98.93% of all initially altered transcripts adapted after 75 s. Only 2.4% of all microgravity-regulated transcripts were sensitive to the cation channel inhibitor SKF-96365. Inter-platform comparison of differentially regulated transcripts revealed 57 annotated gravity-sensitive transcripts. We assume that gravitational forces are rapidly and constantly transduced into the nucleus as omnipresent condition for nuclear and chromatin structure as well as homeostasis of gene expression.
Highlights
The gravitational force has been constant throughout the 4 billion years of Earth’s evolutionary history[1] and played a crucial role in the evolutionary expansion of organisms[2]
Because TRPC1 is activated by stretch[49,50,51], it represents a candidate for transduction of gravitational forces in cells of the MMS
During the parabolic flight campaign (19th DLR PFC), U937 cells were subjected to 20 s of hypergravity (1.8 g) and subsequently to 20 s of microgravity during the first parabola, and samples were obtained at the end of each flight phase
Summary
The gravitational force has been constant throughout the 4 billion years of Earth’s evolutionary history[1] and played a crucial role in the evolutionary expansion of organisms[2]. All terrestrial life has adapted to this fundamental force by developing structures and functions at the levels of organisms, tissues, cells and molecular systems[3], probably including the nucleus, chromatin organization and gene expression[4]. Experiments in microgravity allow to investigate gene expression under force-free conditions and facilitate the elucidation of the role of Earth’s gravity in gene expression homeostasis, while time-resolved studies would help to assess the adaptation potential in an altered gravitational environment. Since gene expression responds very rapidly to altered gravity within or less than minutes[28,29] and force transduction into chromatin requires only seconds[12], initial mechanisms can be studied in the minute range, where different microgravity platforms (parabolic flights, suborbital ballistic rockets) are available for multi-platform analysis at an integrative level[4,29]. The combination of a wide range of ion channel inhibition with whole transcriptome analysis offers the possibility to study the functional role of ion channels in the transduction of gravitation forces at an integrative level
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