scholarly journals Erosion of the Epigenetic Landscape and Loss of Cellular Identity as a Cause of Aging in Mammals

2019 ◽  
Author(s):  
Jae-Hyun Yang ◽  
Patrick T. Griffin ◽  
Daniel L. Vera ◽  
John K. Apostolides ◽  
Motoshi Hayano ◽  
...  
Keyword(s):  
Yeast Cells ◽  
Epigenetic Landscape ◽  
Dna Breaks ◽  
Cell Identity ◽  
Epigenetic Information ◽  
Living Things ◽  
Yeast Aging ◽  
Tissue Changes ◽  
Cellular Identity ◽  
Over Time

SUMMARYAll living things experience entropy, manifested as a loss of inherited genetic and epigenetic information over time. As budding yeast cells age, epigenetic changes result in a loss of cell identity and sterility, both hallmarks of yeast aging. In mammals, epigenetic information is also lost over time, but what causes it to be lost and whether it is a cause or a consequence of aging is not known. Here we show that the transient induction of genomic instability, in the form of a low number of non-mutagenic DNA breaks, accelerates many of the chromatin and tissue changes seen during aging, including the erosion of the epigenetic landscape, a loss of cellular identity, advancement of the DNA methylation clock and cellular senescence. These data support a model in which a loss of epigenetic information is a cause of aging in mammals.One Sentence SummaryThe act of repairing DNA breaks induces chromatin reorganization and a loss of cell identity that may contribute to mammalian aging

scholarly journals Erosion of the Epigenetic Landscape and Loss of Cellular Identity as a Cause of Aging in Mammals

2019 ◽  
Author(s):  
Jae-Hyun Yang ◽  
Patrick T. Griffin ◽  
Daniel L. Vera ◽  
John K. Apostolides ◽  
Motoshi Hayano ◽  
...  
Keyword(s):  
Epigenetic Landscape ◽  
Cellular Identity

Death

Philosophy ◽  
2010 ◽  
Author(s):  
Steven Luper
Keyword(s):  
Moral Issues ◽  
Moral Permissibility ◽  
Persistence Conditions ◽  
Living Things ◽  
Over Time

This article concerns contemporary philosophical discussions of death. The philosophy of death attempts to determine what it is for people and other living things to die, how and the extent to which death and posthumous events benefit or harm those who die, and the morality of killing. The issues that arise might loosely be classified as metaphysical, prudential, and moral. The metaphysical issues concern what death is, and, by extension, what it is to be alive, what you and I are, and what the persistence conditions of living creatures are. (The former issues are covered under the Nature of Death, while the latter are covered under Life and Persistence over Time.) The prudential issues concern how and the extent to which death, posthumous events, and coming to be affect the welfare of those who die (covered under Mortal Harm and Posthumous Harm), and the time when those effects are incurred (covered under The Timing Issue). Finally, the moral issues concern how the prudential significance of death and posthumous events bear on the moral permissibility of killing. When killing is wrong, it is wrong primarily (even if not exclusively) because death harms its victims or because death is imposed on its victims without their consent, which is inconsistent with the respect they are due. Philosophers of death attempt to work out whether and how the harmfulness of dying and consent to being killed bear on the wrongness of killing. (These moral issues are covered under Killing.)

scholarly journals Aberrant Epigenetic Landscape in Cancer: How Cellular Identity Goes Awry

2010 ◽  
Vol 19 (5) ◽  
pp. 698-711 ◽  
Author(s):  
María Berdasco ◽  
Manel Esteller
Keyword(s):  
Epigenetic Landscape ◽  
Cellular Identity

scholarly journals Nonhomologous DNA End-Joining in Plants: Genes and Mechanisms

2001 ◽  
Author(s):  
Clifford F. Weil ◽  
Anne B. Britt ◽  
Avraham Levy
Keyword(s):  
Dna Repair ◽  
Reverse Genetics ◽  
Plant Cells ◽  
Plant Genome ◽  
Yeast Cells ◽  
Dna Breaks ◽  
End Joining ◽  
Modified Dna ◽  
Nonhomologous Dna End Joining ◽  
The U.S

Repair of DNA breaks is an essential function in plant cells as well as a crucial step in addition of modified DNA to plant cells. In addition, our inability to introduce modified DNA to its appropriate locus in the plant genome remains an important hurdle in genetically engineering crop species.We have taken a combined forward and reverse genetics approach to examining DNA double strand break repair in plants, focusing primarily on nonhomologous DNA end-joining. The forward approach utilizes a gamma-plantlet assay (miniature plants that are metabolically active but do not undergo cell division, due to cell cycle arrest) and has resulted in identification of five Arabidopsis mutants, including a new one defective in the homolog of the yeast RAD10 gene. The reverse genetics approach has identified knockouts of the Arabidopsis homologs for Ku80, DNA ligase 4 and Rad54 (one gene in what proves to be a gene family involved in DNA repair as well as chromatin remodeling and gene silencing)). All these mutants have phenotypic defects in DNA repair but are otherwise healthy and fertile. Additional PCR based screens are in progress to find knockouts of Ku70, Rad50, and Mre11, among others. Two DNA end-joining assays have been developed to further our screens and our ability to test candidate genes. One of these involves recovering linearized plasmids that have been added to and then rejoined in plant cells; plasmids are either recovered directly or transformed into E. coli and recovered. The products recovered from various mutant lines are then compared. The other assay involves using plant transposon excision to create DNA breaks in yeast cells and then uses the yeast cell as a system to examine those genes involved in the repair and to screen plant genes that might be involved as well. This award supported three graduate students, one in Israel and two in the U.S., as well as a technician in the U.S., and is ultimately expected to result directly in five publications and one Masters thesis.

scholarly journals Crosslinking actin networks produces compressive force

2019 ◽  
Author(s):  
Rui Ma ◽  
Julien Berro
Keyword(s):  
Actin Filaments ◽  
Brownian Dynamics ◽  
Actin Polymerization ◽  
Turgor Pressure ◽  
Compressive Force ◽  
Yeast Cells ◽  
Actin Networks ◽  
Dynamics Simulations ◽  
Brownian Dynamics Simulations ◽  
Over Time

AbstractActin has been shown to be essential for clathrin-mediated endocytosis in yeast. However, actin polymerization alone is likely insufficient to produce enough force to deform the membrane against the huge turgor pressure of yeast cells. In this paper, we used Brownian dynamics simulations to demonstrate that crosslinking of a meshwork of non-polymerizing actin filaments is able to produce compressive forces. We show that the force can be up to thousands of piconewtons if the crosslinker has a high stiffness. The force decays over time as a result of crosslinker turnover, and is a result of converting chemical binding energy into elastic energy.

scholarly journals Understanding the Impact of Industrial Stress Conditions on Replicative Aging in Saccharomyces cerevisiae

2021 ◽  
Vol 2 ◽  
Author(s):  
Marco Eigenfeld ◽  
Roland Kerpes ◽  
Thomas Becker
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Real Time ◽  
High Throughput ◽  
Stress Conditions ◽  
Yeast Cells ◽  
Industrial Processes ◽  
Non Invasive ◽  
Age Related ◽  
Yeast Aging ◽  
The Impact

In yeast, aging is widely understood as the decline of physiological function and the decreasing ability to adapt to environmental changes. Saccharomyces cerevisiae has become an important model organism for the investigation of these processes. Yeast is used in industrial processes (beer and wine production), and several stress conditions can influence its intracellular aging processes. The aim of this review is to summarize the current knowledge on applied stress conditions, such as osmotic pressure, primary metabolites (e.g., ethanol), low pH, oxidative stress, heat on aging indicators, age-related physiological changes, and yeast longevity. There is clear evidence that yeast cells are exposed to many stressors influencing viability and vitality, leading to an age-related shift in age distribution. Currently, there is a lack of rapid, non-invasive methods allowing the investigation of aspects of yeast aging in real time on a single-cell basis using the high-throughput approach. Methods such as micromanipulation, centrifugal elutriator, or biotinylation do not provide real-time information on age distributions in industrial processes. In contrast, innovative approaches, such as non-invasive fluorescence coupled flow cytometry intended for high-throughput measurements, could be promising for determining the replicative age of yeast cells in fermentation and its impact on industrial stress conditions.

scholarly journals Revealing the Key Regulators of Cell Identity in the Human Adult Pancreas

2020 ◽  
Author(s):  
Lotte Vanheer ◽  
Andrea Alex Schiavo ◽  
Matthias Van Haele ◽  
Tine Haesen ◽  
Adrian Janiszewski ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Cell Types ◽  
List Type ◽  
Cell Identity ◽  
Pancreatic Cell ◽  
Human Adult ◽  
Gene Regulatory ◽  
Cellular Identity

SUMMARYCellular identity during development is under the control of transcription factors that form gene regulatory networks. However, the transcription factors and gene regulatory networks underlying cellular identity in the human adult pancreas remain largely unexplored. Here, we integrate multiple single-cell RNA sequencing datasets of the human adult pancreas, totaling 7393 cells, and comprehensively reconstruct gene regulatory networks. We show that a network of 142 transcription factors forms distinct regulatory modules that characterize pancreatic cell types. We present evidence that our approach identifies key regulators of cell identity in the human adult pancreas. We predict that HEYL and JUND are active in acinar and alpha cells, respectively, and show that these proteins are present in the human adult pancreas as well as in human induced pluripotent stem cell-derived pancreatic cells. The comprehensive gene regulatory network atlas can be explored interactively online. We anticipate our analysis to be the starting point for a more sophisticated dissection of how transcription factors regulate cell identity in the human adult pancreas. Furthermore, given that transcription factors are major regulators of embryo development and are often perturbed in diseases, a comprehensive understanding of how transcription factors work will be relevant in development and disease biology.HIGHLIGHTS-Reconstruction of gene regulatory networks for human adult pancreatic cell types-An interactive resource to explore and visualize gene expression and regulatory states-Predicting putative transcription factors driving pancreatic cell identity-HEYL and JUND as candidate regulators of acinar and alpha cell identity, respectively

scholarly journals Specialization of chromatin-bound nuclear pore complexes promotes yeast aging

2021 ◽  
Author(s):  
Anne C Meinema ◽  
Theo Aspert ◽  
Sung Sik Lee ◽  
Gilles Charvin ◽  
Yves Barral
Keyword(s):  
Quality Control ◽  
Nuclear Pore Complex ◽  
Mrna Export ◽  
Yeast Cells ◽  
Nuclear Pore ◽  
Nuclear Pore Complexes ◽  
Replicative Lifespan ◽  
Yeast Aging ◽  
Key Drivers ◽  
Pore Complexes

The nuclear pore complex (NPC) mediates nearly all exchanges between nucleus and cytoplasm, and changes composition in many species as the organism ages. However, how these changes arise and whether they contribute themselves to aging is poorly understood. We show that in replicatively aging yeast cells attachment of DNA circles to NPCs drives the displacement of the NPCs’ nuclear basket and cytoplasmic complexes. Remodeling of the NPC resulted from the regulation of basket components by SAGA, rather than from damages. These changes affected NPC interaction with mRNA export factors, without affecting the residence of import factors or engaging the NPC quality control machinery. Mutations preventing NPC remodeling extended the replicative lifespan of the cells. Thus, our data indicate that DNA circles accumulating in the mother cell drive aging at least in part by triggering NPC specialization. We suggest that antagonistic pleiotropic effects of NPC specialization are key drivers of aging.

scholarly journals Cellular plasticity at the nexus of development and disease

Development ◽  
2021 ◽  
Vol 148 (3) ◽  
pp. dev197392
Author(s):  
Lillian B. Spatz ◽  
Ramon U. Jin ◽  
Jason C. Mills
Keyword(s):  
Global Health ◽  
Initial Step ◽  
Cell Plasticity ◽  
Cell Identity ◽  
Fields Of Study ◽  
Poster Sessions ◽  
Epigenomic Regulation ◽  
Cellular Identity ◽  
Developmental Contexts ◽  
Identity Changes

ABSTRACTIn October 2020, the Keystone Symposia Global Health Series hosted a Keystone eSymposia entitled ‘Tissue Plasticity: Preservation and Alteration of Cellular Identity’. The event synthesized groundbreaking research from unusually diverse fields of study, presented in various formats, including live and virtual talks, panel discussions and interactive e-poster sessions. The meeting focused on cell identity changes and plasticity in multiple tissues, species and developmental contexts, both in homeostasis and during injury. Here, we review the key themes of the meeting: (1) cell-extrinsic drivers of plasticity; (2) epigenomic regulation of cell plasticity; and (3) conserved mechanisms governing plasticity. A salient take-home conclusion was that there may be conserved mechanisms used by cells to execute plasticity, with autodegradative activity (autophagy and lysosomes) playing a crucial initial step in diverse organs and organisms.

scholarly journals FoxA1 and FoxA2 regulate growth and cellular identity in NKX2-1-positive lung adenocarcinoma

2021 ◽  
Author(s):  
Grace Orstad ◽  
Alex Jones ◽  
Brian Lohman ◽  
Katherine L Gillis ◽  
Eric L Snyder
Keyword(s):  
Lung Adenocarcinoma ◽  
Cancer Progression ◽  
Target Genes ◽  
Marker Genes ◽  
Alveolar Type ◽  
Significant Heterogeneity ◽  
Type I ◽  
Cell Identity ◽  
Genetically Engineered Mouse Model ◽  
Cellular Identity

Change in cancer cell identity is well characterized as a mechanism of cancer progression and acquired resistance to targeted therapies. Lung adenocarcinoma (LUAD) exhibits significant heterogeneity in cell identity and differentiation state; these characteristics correlate directly with prognosis, response to available therapies, and acquisition of drug resistance. In previous work, we have shown that FoxA1 and FoxA2 (FoxA1/2) activate a gastric differentiation program in NKX2-1-negative LUAD. Here we investigate the role of FoxA1/2 in NKX2-1-positive LUAD. We find that FoxA1/2 are consistently expressed in NKX2-1-positive human LUAD. Foxa1/2 deletion severely impairs proliferation and significantly prolongs overall survival in a genetically engineered mouse model of KRAS-driven LUAD. FoxA1/2 activate expression of a mixed-lineage transcriptional program characterized by co-expression of pulmonary (Alveolar Type II) and gastrointestinal marker genes. Loss of FoxA1/2 causes a lineage switch, activating gene expression programs associated with Alveolar Type I cells and maturing squamous epithelial cells. Inhibition of NKX2-1 partially rescues the antiproliferative impact of FoxA1/2 loss, showing that NKX2-1 retains some degree of activity in FoxA1/2-null cells, despite its inability to activate canonical target genes. In summary, this study identifies FoxA1/2 expression as a novel vulnerability in NKX2-1-positive LUAD and shows that FoxA1/2 actively regulate cellular identity in this disease.

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