Transposable elements function as mechanical sensors [CUT&RUN]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE266645 | GEO | 2025/06/30
REPOSITORIES: GEO
Similar Datasets
Project description:Transposable elements (TEs), comprising almost half of the genome, are tightly controlled by intrinsic factors. However, how TEs are modulated by extrinsic mechanical forces remains unknown. To address this question, we culture human embryonic stem cells on hydrogels with different rigidity and comprehensively analyze the changes in transcriptome, epigenome and genome architecture of TEs, and find that TEs are able to sense mechanical forces. Upon sensing changes in substrate rigidity, a majority of TEs exhibit elevated or declined transcription, accompanied by corresponding chromatin state alterations. Moreover, mechanotransducer YAP binds directly to a subset of TEs, especially LTR7/HERV-H, and its loss partly recapitulates effects of soft substrate on TEs. Notably, mechanical forces are required for TEs’ chromatin interaction through YAP and CTCF cooperation. Functionally, mechano-sensing TE-enhancer directs definitive endoderm formation through the regulation of distal target, FAM189A2. Overall, our results demonstrate that TEs are mechanical sensors, and that TE-enhancers dictate cell fate.
2025-06-30 | GSE266648 | GEO
Project description:Transposable elements (TEs), comprising almost half of the genome, are tightly controlled by intrinsic factors. However, how TEs are modulated by extrinsic mechanical forces remains unknown. To address this question, we culture human embryonic stem cells on hydrogels with different rigidity and comprehensively analyze the changes in transcriptome, epigenome and genome architecture of TEs, and find that TEs are able to sense mechanical forces. Upon sensing changes in substrate rigidity, a majority of TEs exhibit elevated or declined transcription, accompanied by corresponding chromatin state alterations. Moreover, mechanotransducer YAP binds directly to a subset of TEs, especially LTR7/HERV-H, and its loss partly recapitulates effects of soft substrate on TEs. Notably, mechanical forces are required for TEs’ chromatin interaction through YAP and CTCF cooperation. Functionally, mechano-sensing TE-enhancer directs definitive endoderm formation through the regulation of distal target, FAM189A2. Overall, our results demonstrate that TEs are mechanical sensors, and that TE-enhancers dictate cell fate.
2025-06-30 | GSE266647 | GEO
Project description:Transposable elements (TEs), comprising almost half of the genome, are tightly controlled by intrinsic factors. However, how TEs are modulated by extrinsic mechanical forces remains unknown. To address this question, we culture human embryonic stem cells on hydrogels with different rigidity and comprehensively analyze the changes in transcriptome, epigenome and genome architecture of TEs, and find that TEs are able to sense mechanical forces. Upon sensing changes in substrate rigidity, a majority of TEs exhibit elevated or declined transcription, accompanied by corresponding chromatin state alterations. Moreover, mechanotransducer YAP binds directly to a subset of TEs, especially LTR7/HERV-H, and its loss partly recapitulates effects of soft substrate on TEs. Notably, mechanical forces are required for TEs’ chromatin interaction through YAP and CTCF cooperation. Functionally, mechano-sensing TE-enhancer directs definitive endoderm formation through the regulation of distal target, FAM189A2. Overall, our results demonstrate that TEs are mechanical sensors, and that TE-enhancers dictate cell fate.
2025-06-30 | GSE266646 | GEO
Project description:Mammalian cells are surrounded by the extracellular matrix (ECM), which regulates intercellular signal transduction and provides structural support to cells. Mechanical forces generated by ECM play a key role in regulating cell behaviors including survival, growth, mobility, and differentiation. However, it is unclear how mechanical forces are sensed by cells and transmit biochemical signals to cell fate-determining transcription factors such as YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif). Here we show the identification of Ras-associated protein 2 (RAP2) as an intracellular signal transducer that senses ECM rigidity and modulates cell survival and growth by negatively regulating YAP/TAZ. Activation of RAP2 by low ECM stiffness or contact inhibition triggers YAP/TAZ phosphorylation. Deletion of RAP2 leads to sustained YAP/TAZ activation in cells that grow on soft matrix or undergo contact inhibition, alters transcription programs initiated by low matrix stiffness, and results in cell transformation and malignant growth. Mechanistically, RAP2 can directly bind to Mitogen-activated protein kinase kinase kinase kinase 4/6/7 (MAP4K4/6/7) or Rho GTPase activating protein 29 (ARHGAP29), both of which lead to LATS1/2 activation and YAP/TAZ inhibition. These findings define a new molecular pathway that transmits mechanical cues to their effectors in the nucleus.
2018-07-09 | GSE98547 | GEO
Project description:Mechanosignaling, initiated by the extracellular physical forces and propagated through the intracellular cytoskeletal network, triggers signaling cascades leading to processes such as embryogenesis, tissue maintenance and disease development. While signal transduction by transcription factors occurs downstream of cellular mechanosensing, nothing is known about the cell intrinsic mechanisms that can regulate mechanosignaling. Here we show that transcription factor PREP1 (PKNOX1) regulates the expression of LINC complex proteins and mechanotransduction of YAP-TAZ. PREP1 depletion upsets the nuclear membrane protein stoichiometry rendering nuclei soft. However, reduced nuclear tension is not conveyed to the cytoplasm, since these cells display fortified actomyosin network with bigger focal adhesion complexes resulting in greater traction forces at the substratum. Intriguingly, YAP-TAZ remains localized to the cytoplasm irrespective of the substrate rigidity indicating disrupted mechanotransduction. Our data demonstrate a hitherto unknown transcriptional mechanism which regulate mechanosignaling upstream of YAP-TAZ transduction.
2022-03-14 | GSE160286 | GEO
Project description:Mechanical cues influence the shape, growth, and function of tissues and organs and are necessary for the development of engineered tissues. Yet, how cells sense mechanical cues and transduce them into changes in gene expression is not well understood. It is known that mechanical forces transmitted to the nucleus induce chromatin remodeling, promote DNA repair, contribute to the motion of intranuclear organelles and cause direct dissociation of protein complexes inside nuclei. Yet, the extent to which such signals impact gene expression is not understood. Because mechanical forces from the cytoskeleton to the nucleus interior are transmitted by the LINC (linker of nucleoskeleton-to-cytoskeleton) complex, we disrupted the LINC complex and performed genome wide expression studies using RNA sequencing. LINC disruption altered the expression of hundreds of genes at a genome-wide scale. We asked how LINC disruption affected the mechanosensitivity of individual genes by quantifying fold changes in gene expression on soft and stiff substrates. Remarkably, LINC disruption tended to preserve gene mechanosensitivity, but to reverse its direction. LINC disruption did not cause changes in nuclear shape, nor eliminated nuclear shape sensitivity to substrate rigidity. Our results show for the first time that the LINC complex regulates mechano-sensing at a genome-wide level, and argue for a distinct mechanism that does not require changes in nuclear morphology.
2017-01-20 | GSE77520 | GEO
Project description:Mechanical cues influence the shape, growth, and function of tissues and organs and are necessary for the development of engineered tissues. Yet, how cells sense mechanical cues and transduce them into changes in gene expression is not well understood. It is known that mechanical forces transmitted to the nucleus induce chromatin remodeling, promote DNA repair, contribute to the motion of intranuclear organelles and cause direct dissociation of protein complexes inside nuclei. Yet, the extent to which such signals impact gene expression is not understood. Because mechanical forces from the cytoskeleton to the nucleus interior are transmitted by the LINC (linker of nucleoskeleton-to-cytoskeleton) complex, we disrupted the LINC complex and performed genome wide expression studies using RNA sequencing. LINC disruption altered the expression of hundreds of genes at a genome-wide scale. We asked how LINC disruption affected the mechanosensitivity of individual genes by quantifying fold changes in gene expression on soft and stiff substrates. Remarkably, LINC disruption tended to preserve gene mechanosensitivity, but to reverse its direction. LINC disruption did not cause changes in nuclear shape, nor eliminated nuclear shape sensitivity to substrate rigidity. Our results show for the first time that the LINC complex regulates mechano-sensing at a genome-wide level, and argue for a distinct mechanism that does not require changes in nuclear morphology.
2017-01-20 | GSE77472 | GEO
Project description:Endothelial cells (ECs) are constantly exposed to mechanical forces in the form of fluid shear stress, extracellular stiffness, and cyclic strain. How mechanical forces are transduced to the nucleus to drive transcriptional reprogramming in ECs is poorly understood. The mechanoresponsive activity of Yes associated protein (YAP) and its role in vascular development are well described, however, whether changes to transcription or epigenetic regulation of YAP are involved in these processes remains unanswered. Our results reveal that mechanical forces sensed at cell-cell junctions by the YAP target gene, Angiomotin-like 2 (AmotL2), are directly intervened into changes in global chromatin accessibility and EZH2 activity leading to modulation of YAP-promotor activity. Functionally, shear stress induced proliferation of ECs in vivo were reliant on AmotL2 and YAP/TAZ endothelial expression. Mechanistically, uncoupling of the nuclear-cytoskeletal connection from junctions and focal adhesions led to altered nuclear morphology, chromatin accessibility and suppression of YAP-promotor activity. Our findings reveal a role for AmotL2 and nuclear-cytoskeletal force transmission in modulating the epigenetic and transcriptional regulation of YAP to maintain a mechanoenforced positive-feedback loop of vascular homeostasis.
2024-01-23 | GSE253761 | GEO
Project description:Cells are subjected to dynamic mechanical environments which impart forces and induce cellular responses. In age-related conditions like pulmonary fibrosis, there is both an increase in tissue stiffness and an accumulation of senescent cells. While senescent cells produce a senescence-associated secretory phenotype (SASP), the impact of physical stimuli on both cellular senescence and the SASP is not well understood. Here, we show that mechanical tension, modeled using cell culture substrate rigidity, influences senescent cell markers like SA-β-gal and secretory phenotypes. Comparing human primary pulmonary fibroblasts (IMR-90) cultured on physiological (2 kPa), fibrotic (50 kPa), and plastic (approximately 3 GPa) substrates, followed by senescence induction using doxorubicin, we identified unique high-stiffness-driven secretory protein profiles using mass spectrometry and transcriptomic signatures, both showing an enrichment in collagen proteins. Consistently, clusters of p21+ cells are seen in fibrotic regions of bleomycin induced pulmonary fibrosis in mice. Computational meta-analysis of single-cell RNA sequencing datasets from human interstitial lung disease confirmed these stiffness SASP genes are highly expressed in disease fibroblasts and strongly correlate with mechanotransduction and senescence-related pathways. Thus, mechanical forces shape cell senescence and their secretory phenotypes.
2025-01-21 | GSE282384 | GEO
Project description:During plant vascular development, xylem tracheary elements (TEs) form water conducting, empty pipes through genetically regulated cell death. Cell death is prevented from spreading to non-TEs by unidentified intercellular mechanisms, downstream of METACASPASE9 (MC9)-mediated regulation of autophagy in TEs. Here, we identified differentially abundant extracellular peptides in vascular11 differentiating wild type and MC9-downregulated Arabidopsis cell suspensions. The peptide Kratos rescued the abnormally high ectopic non-TE death resulting from either MC9 knockout or TE-specific overexpression of the ATG5 autophagy protein during experimentally induced vascular differentiation in Arabidopsis cotyledons. Kratos also reduced cell death following mechanical damage and extracellular ROS production in Arabidopsis leaves. Stress-induced but not vascular non-TE cell death was enhanced by another identified peptide, Bia. Bia is therefore reminiscent of several known plant cell death-inducing peptides acting as damage-associated molecular patterns. In contrast, Kratos plays a novel extracellular cell survival role in the context of development and during stress response.
2019-01-31 | PXD010886 | Pride