scholarly journals An epigenetic landscape governs early fate decision in cellular aging

2019 ◽  
Author(s):  
Yang Li ◽  
Yanfei Jiang ◽  
Julie Paxman ◽  
Richard O’Laughlin ◽  
Lorraine Pillus ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Cell Fate ◽  
Quantitative Model ◽  
Cellular Aging ◽  
Multiple Equilibrium ◽  
Epigenetic Landscape ◽  
Genetically Engineer ◽  
Different Types ◽  
Extended Lifespan ◽  
Fate Decision

AbstractChromatin instability and mitochondrial decline are conserved processes that contribute to cellular aging. Although both processes have been explored individually in the context of their distinct signaling pathways, the mechanism that determines which cell fate arises in isogenic cells is unknown. Here, we show that interactions between the chromatin silencing and mitochondrial pathways lead to an epigenetic landscape with multiple equilibrium states that represent different types of terminal cellular states. Interestingly, the structure of the landscape drives single-cell differentiation towards one of these states during aging, whereby the fate is determined quite early and is insensitive to intracellular noise. Guided by a quantitative model of the aging landscape, we genetically engineer a new “long-lived” equilibrium state that is characterized by a dramatically extended lifespan.

scholarly journals A programmable fate decision landscape underlies single-cell aging in yeast

Science ◽  
2020 ◽  
Vol 369 (6501) ◽  
pp. 325-329 ◽  
Author(s):  
Yang Li ◽  
Yanfei Jiang ◽  
Julie Paxman ◽  
Richard O’Laughlin ◽  
Stephen Klepin ◽  
...  
Keyword(s):  
Single Cell ◽  
Quantitative Model ◽  
Genetically Engineered ◽  
Cellular Aging ◽  
Multiple Equilibrium ◽  
Cell Aging ◽  
Epigenetic Landscape ◽  
Replicative Aging ◽  
Different Types ◽  
Fate Decision

Chromatin instability and mitochondrial decline are conserved processes that contribute to cellular aging. Although both processes have been explored individually in the context of their distinct signaling pathways, the mechanism that determines which process dominates during aging of individual cells is unknown. We show that interactions between the chromatin silencing and mitochondrial pathways lead to an epigenetic landscape of yeast replicative aging with multiple equilibrium states that represent different types of terminal states of aging. The structure of the landscape drives single-cell differentiation toward one of these states during aging, whereby the fate is determined quite early and is insensitive to intracellular noise. Guided by a quantitative model of the aging landscape, we genetically engineered a long-lived equilibrium state characterized by an extended life span.

scholarly journals Epigenetic Landscape Models: The Post-Genomic Era

2014 ◽  
Author(s):  
Jose Davila-Velderrain ◽  
Juan Carlos Martinez-Garcia ◽  
Elena R Alvarez-Buylla
Keyword(s):  
Cell Differentiation ◽  
Cell Fate ◽  
Regulatory Networks ◽  
Computational Models ◽  
Theoretical Models ◽  
Cell Types ◽  
State Transitions ◽  
Epigenetic Landscape ◽  
Cell Fate Decisions ◽  
Landscape Models

Complex networks of regulatory interactions orchestrate developmental processes in multicellular organisms. Such a complex internal structure intrinsically constrains cellular behavior allowing only a reduced set of attainable and observable cellular states or cell types. Thus, a multicellular system undergoes cell fate decisions in a robust manner in the course of its normal development. The epigenetic landscape (EL) model originally proposed by C.H. Waddington was an early attempt to integrate these processes in a universal conceptual model of development. Since then, a wealth of experimental data has accumulated, the general mechanisms of gene regulation have been uncovered, and the placement of specific molecular components within modular gene regulatory networks (GRN) has become a common practice. This has motivated the development of mathematical and computational models inspired by the EL aiming to integrate molecular data and gain a better understanding of development, and hopefully predict cell differentiation and reprogramming events. Both deterministic and stochastic dynamical models have been used to described cell state transitions. In this review, we describe recent EL models, emphasising that the construction of an explicit landscape from a GRN is not the only way to implement theoretical models consistent with the conceptual basis of the EL. Moreover, models based on the EL have been shown to be useful in the study of morphogenic processes and not just cell differentiation. Here we describe the distinct approaches, comparing their strengths and weaknesses and the kind of biological questions that they have been able to address. We also point to challenges ahead.

scholarly journals Branching and oscillations in the epigenetic landscape of cell-fate determination

2014 ◽  
Author(s):  
Jomar Fajardo Rabajante ◽  
Ariel Lagdameo Babierra
Keyword(s):  
Gene Regulation ◽  
Cell Differentiation ◽  
Cell Fate ◽  
Type System ◽  
Cellular Reprogramming ◽  
Cell Fate Determination ◽  
State Variables ◽  
Epigenetic Landscape ◽  
Alternative Scheme ◽  
Fate Determination

The well-known Waddington?s epigenetic landscape of cell-fate determination is not static but varies because of the dynamic gene regulation during development. However, existing mathematical models with few state variables and fixed parameters are inadequate in characterizing the temporal transformation of the landscape. Here we simulate a decision-switch model of gene regulation with more than two state variables and with time-varying repression among regulatory factors. We are able to demonstrate multi-lineage differentiation at different timescales that portrays the branching canals in Waddington?s illustration. We also present a repressilator-type system that activates suppressed genes via sustained oscillations in a flattened landscape, hence providing an alternative scheme for cellular reprogramming. The time-dependent parameters governed by gradient-based dynamics regulate cell differentiation, dedifferentiation and transdifferentiation. Our prediction integrates the theories of branching and structural oscillations in cell-fate determination, which reveals key temporal patterns of cell differentiation and associated diseases, such as cancer. Keywords: gene regulatory network, stem cells, pluripotency, synthetic biology, multistability, attractor Note: This paper has been accepted for publication in Progress in Biophysics and Molecular Biology (Elsevier). DOI of the peer-reviewed manuscript: 10.1016/j.pbiomolbio.2015.01.006

scholarly journals Epigenetic dynamics shaping melanophore and iridophore cell fate in zebrafish

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Hyo Sik Jang ◽  
Yujie Chen ◽  
Jiaxin Ge ◽  
Alicia N. Wilkening ◽  
Yiran Hou ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
Neural Crest ◽  
Cell Fate ◽  
Pigment Cell ◽  
Chromatin Accessibility ◽  
Pigment Cells ◽  
Epigenetic Landscape ◽  
Cell Fate Decisions ◽  
Neural Crest Differentiation

Abstract Background Zebrafish pigment cell differentiation provides an attractive model for studying cell fate progression as a neural crest progenitor engenders diverse cell types, including two morphologically distinct pigment cells: black melanophores and reflective iridophores. Nontrivial classical genetic and transcriptomic approaches have revealed essential molecular mechanisms and gene regulatory circuits that drive neural crest-derived cell fate decisions. However, how the epigenetic landscape contributes to pigment cell differentiation, especially in the context of iridophore cell fate, is poorly understood. Results We chart the global changes in the epigenetic landscape, including DNA methylation and chromatin accessibility, during neural crest differentiation into melanophores and iridophores to identify epigenetic determinants shaping cell type-specific gene expression. Motif enrichment in the epigenetically dynamic regions reveals putative transcription factors that might be responsible for driving pigment cell identity. Through this effort, in the relatively uncharacterized iridophores, we validate alx4a as a necessary and sufficient transcription factor for iridophore differentiation and present evidence on alx4a’s potential regulatory role in guanine synthesis pathway. Conclusions Pigment cell fate is marked by substantial DNA demethylation events coupled with dynamic chromatin accessibility to potentiate gene regulation through cis-regulatory control. Here, we provide a multi-omic resource for neural crest differentiation into melanophores and iridophores. This work led to the discovery and validation of iridophore-specific alx4a transcription factor.

scholarly journals E2A-regulated epigenetic landscape promotes memory CD8 T cell differentiation

2021 ◽  
Vol 118 (16) ◽  
pp. e2013452118
Author(s):  
David M. Schauder ◽  
Jian Shen ◽  
Yao Chen ◽  
Moujtaba Y. Kasmani ◽  
Matthew R. Kudek ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cell Fate ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Differentiation ◽  
Effector Cells ◽  
Memory Cd8 T Cell ◽  
Fate Decision

During an acute viral infection, CD8 T cells encounter a myriad of antigenic and inflammatory signals of variable strength, which sets off individual T cells on their own differentiation trajectories. However, the developmental path for each of these cells will ultimately lead to one of only two potential outcomes after clearance of the infection—death or survival and development into memory CD8 T cells. How this cell fate decision is made remains incompletely understood. In this study, we explore the transcriptional changes during effector and memory CD8 T cell differentiation at the single-cell level. Using single-cell, transcriptome-derived gene regulatory network analysis, we identified two main groups of regulons that govern this differentiation process. These regulons function in concert with changes in the enhancer landscape to confer the establishment of the regulatory modules underlying the cell fate decision of CD8 T cells. Furthermore, we found that memory precursor effector cells maintain chromatin accessibility at enhancers for key memory-related genes and that these enhancers are highly enriched for E2A binding sites. Finally, we show that E2A directly regulates accessibility of enhancers of many memory-related genes and that its overexpression increases the frequency of memory precursor effector cells and accelerates memory cell formation while decreasing the frequency of short-lived effector cells. Overall, our results suggest that effector and memory CD8 T cell differentiation is largely regulated by two transcriptional circuits, with E2A serving as an important epigenetic regulator of the memory circuit.

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