Assoziation schneller Reaktionen der Genexpression mit Änderungen der 3D-Chromatinkonformation in veränderter Schwerkraft

ZUSAMMENFASSUNG

Die molekularen Prinzipien bei der Transduktion von Schwerkraftänderungen in zelluläre Antwort- und Anpassungsprozesse sind bisher weitgehend unbekannt. Wir konnten in humanen Jurkat-T-Zellen zeigen, dass Gene bei veränderter Schwerkraft in Clusterstrukturen („gravity-responsive chromosomal regions“, GRCRs) differenziell reguliert werden. Durch Kombination mit Hochdurchsatz-Chromatin-Konformationsanalysen (Hi-C) konnte eine hochsignifikante Assoziation von GRCRs mit strukturellen 3D-Chromatinveränderungen identifiziert werden, die vor allem auf den kleinen Chromosomen (chr16–chr22) kolokalisieren. Wir fanden weiterhin Hinweise auf einen mechanistischen Zusammenhang zwischen Spleißprozessen und differenzieller Genexpression bei veränderter Schwerkraft. Somit haben wir erste Belege dafür gefunden, dass Änderungen der Schwerkraft in den Zellkern übertragen werden und dort 3D-Chromosomen-Konformationsänderungen hervorrufen, die mit einer schnellen Transkriptionsantwort verbunden sind. Wir vermuten, dass die schnelle genomische Antwort auf veränderte Gravitationskräfte in der Organisation des Chromatins spezifisch codiert ist.

ABSTRACT

The molecular principles involved in the transduction of gravity changes into cellular response and adaptation processes are largely unknown. We have shown in human Jurkat T cells that genes are differentially regulated in cluster structures (“gravity-responsive chromosomal regions”, GRCRs) upon gravity change. Combined with high-throughput chromatin conformation capture (Hi-C) analysis (Hi-C), we identified a highly significant association of GRCRs with structural 3D chromatin changes that colocalize primarily on the small chromosomes (chr16–chr22). We further found evidence for a mechanistic link between splicing processes and differential gene expression under altered gravity. Thus, we found first evidence that gravitational changes are transmitted to the nucleus, where they induce 3D chromosome conformational changes associated with a rapid transcriptional response. We suggest that the rapid genomic response to altered gravitational forces is specifically encoded in the spatial chromatin organization.

Key words

microgravity - gene expression - chromatin - adaptation

Publikationsverlauf

Artikel online veröffentlicht:
10. Oktober 2022

• Literatur

• 1 Hemmersbach R, Braun M.. Gravity-sensing and gravity-related signaling pathways in unicellular model systems of protists and plants. Signal Transduction 2006; 06: 432-442 DOI: 10.1002/sita.200600106.
• 2 Häder DP, Braun M, Grimm D. et al Gravireceptors in eukaryotes-a comparison of case studies on the cellular level. NPJ Microgravity 2017; 03: 13 DOI: 10.1038/s41526-017-0018-8.
• 3 Vorselen D, Roos WH, MacKintosh FC. et al The role of the cytoskeleton in sensing changes in gravity by nonspecialized cells. FASEB J 2014; 28: 536-547 DOI: 10.1096/fj.13-236356.
• 4 Ullrich O, Thiel CS. Cellular and Molecular Responses to Gravitational Force-Triggered Stress in Cells of the Immune System. In: Choukér A (ed.). Stress Challenges and Immunity in Space. 2nd ed. Springer 2020: 301-325
• 5 Thiel CS, Hauschild S, Huge A. et al Dynamic gene expression response to altered gravity in human T cells. Sci Rep 2017: 5204 DOI: 10.1038/s41598-017-05580-x
• 6 Thiel CS, Christoffel S, Tauber S. et al Rapid Cellular Perception of Gravitational Forces in Human Jurkat T Cells and Transduction into Gene Expression Regulation. Int J Mol Sci 2020; 21: 514 DOI: 10.3390/ijms21020514.
• 7 Thiel CS, Huge A, Hauschild S. et al Stability of gene expression in human T cells in different gravity environments is clustered in chromosomal region 11p15.4. NPJ Microgravity 2017; 03: 22 DOI: 10.1038/s41526-017-0028-6.
• 8 Thiel CS, Hauschild S, Tauber S. et al Identification of reference genes in human myelomonocytic cells for gene expression studies in altered gravity. Biomed Res Int 2015; 2015: 363575 DOI: 10.1155/2015/363575.
• 9 Gaidatzis D, Burger L, Florescu M. et al Analysis of intronic and exonic reads in RNA-seq data characterizes transcriptional and post-transcriptional regulation. Nat Biotechnol 2015; 33: 722-729 DOI: 10.1038/nbt.3269.
• 10 Amrichová J, Lukásová E, Kozubek S. et al Nuclear and territorial topography of chromosome telomeres in human lymphocytes. Exp Cell Res 2003; 289: 11-26 DOI: 10.1016/s0014-4827(03)00208-8.
• 11 Bolzer A, Kreth G, Solovei I, et al.. Three-dimensional maps of all chromosomes in human male fibroblast nuclei and prometaphase rosettes. PLoS Biol 2005; 03: e157 DOI: 10.1371/journal.pbio.0030157.
• 12 Vahlensieck C, Thiel CS, Zhan Y. et al Gravitational Force-Induced 3D Chromosomal Conformational Changes Are Associated with Rapid Transcriptional Response in Human T Cells. Int J Mol Sci 2021; 22: 9426 DOI: 10.3390/ijms22179426.
• 13 Ullrich O.. 4th Swiss Parabolic Flight Campaign. Flug u Reisemed 2020; 27: 247-252 DOI: 10.1055/a-1248-5679.
• 14 Vahlensieck C, Thiel CS, Pöschl D. et al Post-Transcriptional Dynamics is Involved in Rapid Adaptation to Hypergravity in Jurkat T Cells. Front Cell Dev Biol 2022; 10: 933984 DOI: 10.3389/fcell.2022.933984.
• 15 Milo R, Phillips R. Cell Biology by the Numbers. New York: Garland Science; 2015
• 16 La Manno G, Soldatov R, Zeisel A. et al RNA velocity of single cells. Nature 2018; 560: 494-498 DOI: 10.1038/s41586-018-0414-6.
• 17 Tajik A, Zhang Y, Wei F. et al Transcription upregulation via force-induced direct stretching of chromatin. Nat Mater 2016; 15: 1287-1296 DOI: 10.1038/nmat4729.
• 18 Athirasala A, Hirsch N, Buxboim A. Nuclear mechanotransduction: sensing the force from within. Curr Opin Cell Biol 2017; 46: 119-127 DOI: 10.1016/j.ceb.2017.04.004.
• 19 Thorpe SD, Lee DA. Dynamic regulation of nuclear architecture and mechanics-a rheostatic role for the nucleus in tailoring cellular mechanosensitivity. Nucleus 2017; 08: 287-300 DOI: 10.1080/19491034.2017.1285988.
• 20 Najrana T, Sanchez-Esteban J. Mechanotransduction as an Adaptation to Gravity. Front Pediatr 2016; 04: 140 DOI: 10.3389/fped.2016.00140.
• 21 Uhler C, Shivashankar GV. Regulation of genome organization and gene expression by nuclear mechanotransduction. Nat Rev Mol Cell Biol 2017; 18: 717-727 DOI: 10.1038/nrm.2017.101.
• 22 Thiel CS, Tauber S, Lauber B. et al Rapid Morphological and Cytoskeletal Response to Microgravity in Human Primary Macrophages. Int J Mol Sci 2019; 20: 2402 DOI: 10.3390/ijms20102402.
• 23 Ingber DE. Cellular mechanotransduction: putting all the pieces together again. FASEB J 2006; 20: 811-827 DOI: 10.1096/fj.05-5424rev.
• 24 Ingber DE. Tensegrity-based mechanosensing from macro to micro. Prog Biophys Mol Biol 2008; 97: 163-179 DOI: 10.1016/j.pbiomolbio.2008.02.005.
• 25 Belaadi N, Aureille J, Guilluy C. Under Pressure: Mechanical Stress Management in the Nucleus. Cells 2016; 05: 27 DOI: 10.3390/cells5020027.
• 26 Fedorchak GR, Kaminski A, Lammerding J. Cellular mechanosensing: getting to the nucleus of it all. Prog Biophys Mol Biol 2014; 115: 76-92 DOI: 10.1016/j.pbiomolbio.2014.06.009.
• 27 Navarro AP, Collins MA, Folker ES. The nucleus is a conserved mechanosensation and mechanoresponse organelle. Cytoskeleton (Hoboken) 2016; 73: 59-67 DOI: 10.1002/cm.21277.
• 28 Le HQ, Ghatak S, Yeung CY. et al Mechanical regulation of transcription controls Polycomb-mediated gene silencing during lineage commitment. Nat Cell Biol 2016; 18: 864-875 DOI: 10.1038/ncb3387.
• 29 Makhija E, Jokhun DS, Shivashankar GV. Nuclear deformability and telomere dynamics are regulated by cell geometric constraints. Proc Natl Acad Sci U S A 2016; 113: E32-E40 DOI: 10.1073/pnas.1513189113.
• 30 Wang Y, Nagarajan M, Uhler C. et al Orientation and repositioning of chromosomes correlate with cell geometry-dependent gene expression. Mol Biol Cell 2017; 28: 1997-2009 DOI: 10.1091/mbc.E16-12-0825.
• 31 Stein GS, van Wijnen AJ, Stein JL. et al Implications for interrelationships between nuclear architecture and control of gene expression under microgravity conditions. FASEB J 1999; 13 Suppl S157-S166 DOI: 10.1096/fasebj.13.9001.s157.