scholarly journals A stochastic epigenetic switch controls the dynamics of T-cell lineage commitment

2018 ◽  
Author(s):  
Kenneth K.H. Ng ◽  
Mary A. Yui ◽  
Arnav Mehta ◽  
Sharmayne Siu ◽  
Blythe Irwin ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
Fluorescent Proteins ◽  
Cell Lineage ◽  
Distal Enhancer ◽  
Epigenetic Switch ◽  
Individual Gene ◽  
Cell Fate Decisions ◽  
Genetic Perturbations ◽  
Tightly Coupled

SummaryCell fate decisions occur through the switch-like, irreversible activation of fate-specifying genes. These activation events are often assumed to be tightly-coupled to changes in upstream transcription factors, but could also be constrained by cis-epigenetic mechanisms at individual gene loci. Here, we studied the activation of Bcl11b, which controls T-cell fate commitment. To disentangle cis and trans effects, we generated mice where two Bcl11b copies are tagged with distinguishable fluorescent proteins. Quantitative live microscopy of progenitors from these mice revealed that Bcl11b turned on after a stochastic delay averaging multiple days, which varied not only between cells but also between Bcl11b alleles within the same cell. Genetic perturbations, together with mathematical modeling, showed that a distal enhancer controls the rate of epigenetic activation, while a parallel Notch-dependent trans-acting step stimulates expression from activated loci. These results show that developmental fate transitions can be controlled by stochastic cis-acting events on individual loci.

scholarly journals A stochastic epigenetic switch controls the dynamics of T-cell lineage commitment

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Kenneth KH Ng ◽  
Mary A Yui ◽  
Arnav Mehta ◽  
Sharmayne Siu ◽  
Blythe Irwin ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
Fluorescent Proteins ◽  
Cell Lineage ◽  
Distal Enhancer ◽  
Epigenetic Switch ◽  
Individual Gene ◽  
Cis Acting ◽  
Cell Fate Decisions ◽  
Tightly Coupled

Cell fate decisions occur through the switch-like, irreversible activation of fate-specifying genes. These activation events are often assumed to be tightly coupled to changes in upstream transcription factors, but could also be constrained by cis-epigenetic mechanisms at individual gene loci. Here, we studied the activation of Bcl11b, which controls T-cell fate commitment. To disentangle cis and trans effects, we generated mice where two Bcl11b copies are tagged with distinguishable fluorescent proteins. Quantitative live microscopy of progenitors from these mice revealed that Bcl11b turned on after a stochastic delay averaging multiple days, which varied not only between cells but also between Bcl11b alleles within the same cell. Genetic perturbations, together with mathematical modeling, showed that a distal enhancer controls the rate of epigenetic activation, while a parallel Notch-dependent trans-acting step stimulates expression from activated loci. These results show that developmental fate transitions can be controlled by stochastic cis-acting events on individual loci.

Critical Functions for Notch Dimerization In T Cell Transformation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3647-3647
Author(s):  
Hudan Liu ◽  
Anthony Chi ◽  
Kelly Arnett ◽  
Mark Chiang ◽  
Lanwei Xu ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Cell Transformation ◽  
Conflicts Of Interest ◽  
Cell Lineage ◽  
Differential Sensitivity ◽  
Cell Fate Decisions ◽  
Order Complexes

Abstract Abstract 3647 Notch1 encodes an essential transmembrane receptor that is frequently mutated in T-ALL. Notch signaling regulates cell fate decisions, proliferation, survival and metabolism by activating transcription; yet the mechanism by which Notch selectively activates different transcriptional targets is poorly understood. After ligand-induced proteolysis, the intracellular part of Notch (ICN) generates signals by entering the nucleus and forming a transcriptional activation complex with the transcription factor CSL and the co-activator Mastermind (MAML). This complex can bind DNA as a monomer [1-3], however it can also dimerize on sites in which a pair of head-to-head CSL binding sites is properly spaced (so-called paired sites) [4, 5]. Whether Notch dimerization is physiologically important is unknown. Using T cell development and transformation as models, we now report that dimeric Notch transcriptional complexes are required for leukemic transformation but dispensable for T cell fate specification from a multipotential precursor. The varying requirements for Notch dimerization within the T cell lineage result from the differential sensitivity of specific Notch target genes. One particularly important dimerization-dependent target of Notch, required for both T cell maturation and leukemogenesis, is the proto-oncogene c-Myc, whereas other well-characterized target genes, such as Hey1, show no dimerization-dependence. These findings identify functionally important differences in the responsiveness among Notch target genes attributable to the formation of higher-order complexes. Our data suggest that it may be possible to develop a new class of Notch inhibitors, which selectively block outcomes that are dependent on Notch dimerization (e.g., leukemogenesis). References: 1. Nam, Y., et al., J Biol Chem, 2003. 278: 21232. 2. Nam, Y., et al., Cell, 2006. 124: 973. 3. Wilson, J.J. and R.A. Kovall, Cell, 2006. 124: 985. 4. Bailey, A.M. and J.W. Posakony, Genes Dev, 1995. 9: 2609. 5. Nam, Y., et al., Proc Natl Acad of Sci USA, 2007. 104: 2103. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Cell fate clusters in ICM organoids arise from cell fate heredity and division: a modelling approach

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Tim Liebisch ◽  
Armin Drusko ◽  
Biena Mathew ◽  
Ernst H. K. Stelzer ◽  
Sabine C. Fischer ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Division ◽  
Cell Fate ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Cell Lineage ◽  
Cell Fate Decision ◽  
Cell Fate Decisions ◽  
Chemical Signalling ◽  
Fate Decision

AbstractDuring the mammalian preimplantation phase, cells undergo two subsequent cell fate decisions. During the first decision, the trophectoderm and the inner cell mass are formed. Subsequently, the inner cell mass segregates into the epiblast and the primitive endoderm. Inner cell mass organoids represent an experimental model system, mimicking the second cell fate decision. It has been shown that cells of the same fate tend to cluster stronger than expected for random cell fate decisions. Three major processes are hypothesised to contribute to the cell fate arrangements: (1) chemical signalling; (2) cell sorting; and (3) cell proliferation. In order to quantify the influence of cell proliferation on the observed cell lineage type clustering, we developed an agent-based model accounting for mechanical cell–cell interaction, i.e. adhesion and repulsion, cell division, stochastic cell fate decision and cell fate heredity. The model supports the hypothesis that initial cell fate acquisition is a stochastically driven process, taking place in the early development of inner cell mass organoids. Further, we show that the observed neighbourhood structures can emerge solely due to cell fate heredity during cell division.

scholarly journals Lineage Switching in Acute Leukemias: A Consequence of Stem Cell Plasticity?

2012 ◽  
Vol 2012 ◽  
pp. 1-18 ◽  
Author(s):  
Elisa Dorantes-Acosta ◽  
Rosana Pelayo
Keyword(s):  
Cell Fate ◽  
High Efficiency ◽  
Current Knowledge ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Cell Lineage ◽  
Leukemic Cells ◽  
Acute Leukemias ◽  
Cell Fate Decisions ◽  
Lineage Switch

Acute leukemias are the most common cancer in childhood and characterized by the uncontrolled production of hematopoietic precursor cells of the lymphoid or myeloid series within the bone marrow. Even when a relatively high efficiency of therapeutic agents has increased the overall survival rates in the last years, factors such as cell lineage switching and the rise of mixed lineages at relapses often change the prognosis of the illness. During lineage switching, conversions from lymphoblastic leukemia to myeloid leukemia, or vice versa, are recorded. The central mechanisms involved in these phenomena remain undefined, but recent studies suggest that lineage commitment of plastic hematopoietic progenitors may be multidirectional and reversible upon specific signals provided by both intrinsic and environmental cues. In this paper, we focus on the current knowledge about cell heterogeneity and the lineage switch resulting from leukemic cells plasticity. A number of hypothetical mechanisms that may inspire changes in cell fate decisions are highlighted. Understanding the plasticity of leukemia initiating cells might be fundamental to unravel the pathogenesis of lineage switch in acute leukemias and will illuminate the importance of a flexible hematopoietic development.

scholarly journals Regulation and function of mTOR signalling in T cell fate decisions

2012 ◽  
Vol 12 (5) ◽  
pp. 325-338 ◽  
Author(s):  
Hongbo Chi
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
Cell Fate Decisions ◽  
And Function ◽  
Mtor Signalling

Pax5 determines B- versus T-cell fate and does not block early myeloid-lineage development

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4342-4346 ◽  
Author(s):  
Claudiu V. Cotta ◽  
Zheng Zhang ◽  
Hyung-Gyoon Kim ◽  
Christopher A. Klug
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Nk Cell ◽  
Cell Lineage ◽  
Blood Analysis ◽  
Hematopoietic Stem ◽  
Peripheral Blood Analysis

Abstract Progenitor B cells deficient in Pax5 are developmentally multipotent, suggesting that Pax5 is necessary to maintain commitment to the B-cell lineage. Commitment may be mediated, in part, by Pax5 repression of myeloid-specific genes. To determine whether Pax5 expression in multipotential cells is sufficient to restrict development to the B-cell lineage in vivo, we enforced expression of Pax5 in hematopoietic stem cells using a retroviral vector. Peripheral blood analysis of all animals reconstituted with Pax5-expressing cells indicated that more than 90% of Pax5-expressing cells were B220+ mature B cells that were not malignant. Further analysis showed that Pax5 completely blocked T-lineage development in the thymus but did not inhibit myelopoiesis or natural killer (NK) cell development in bone marrow. These results implicate Pax5 as a critical regulator of B- versus T-cell developmental fate and suggest that Pax5 may promote commitment to the B-cell lineage by mechanisms that are independent of myeloid gene repression.

scholarly journals ERG orchestrates chromatin interactions to drive prostate cell fate reprogramming

2020 ◽  
Author(s):  
Fei Li ◽  
Qiuyue Yuan ◽  
Wei Di ◽  
Xinyi Xia ◽  
Zhuang Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Fate ◽  
Early Stage ◽  
Cell Lineage ◽  
Basal Cells ◽  
Distal Enhancer ◽  
Enhancer Activity ◽  
Prostate Cell ◽  
Knock Out ◽  
Chromatin Interactions

AbstractWhile cancer is commonly perceived as a disease of dedifferentiation, the hallmark of early stage prostate cancer is paradoxically the loss of more plastic basal cells and the abnormal proliferation of more differentiated secretory luminal cells. However, the mechanism of prostate cancer pro-luminal differentiation is largely unknown. Through integrating analysis of the transcription factors (TFs) from 806 human prostate cancers, we have identified that ERG highly correlated with prostate cancer luminal subtyping. ERG overexpression in luminal epithelial cells inhibits its normal plasticity to transdifferentiate into basal lineage and ERG supersedes PTEN-loss which favors basal differentiation. ERG knock-out disrupted prostate cell luminal differentiation, whereas AR knock-out had no such effects. Trp63 is a known master regulator of prostate basal lineage. Through analysis of 3D chromatin architecture, we found that ERG binds and inhibits the enhancer activity and chromatin looping of a Trp63 distal enhancer, thereby silencing its gene expression. Specific deletion of the distal ERG binding site resulted in the loss of ERG-mediated inhibition of basal differentiation. Thus, ERG orchestrates chromatin interactions and regulates prostate cell lineage toward pro-luminal program, as its fundamental role on lineage differentiation in prostate cancer initiation.

scholarly journals The Hypoxia-Inducible Factor Pathway, Prolyl Hydroxylase Domain Protein Inhibitors, and Their Roles in Bone Repair and Regeneration

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Lihong Fan ◽  
Jia Li ◽  
Zefeng Yu ◽  
Xiaoqian Dang ◽  
Kunzheng Wang
Keyword(s):  
Cell Fate ◽  
Bone Repair ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Bone Tumours ◽  
Cell Fate Decisions ◽  
Tightly Coupled ◽  
Hif Pathway ◽  
Prolyl Hydroxylase Domain

Hypoxia-inducible factors (HIFs) are oxygen-dependent transcriptional activators that play crucial roles in angiogenesis, erythropoiesis, energy metabolism, and cell fate decisions. The group of enzymes that can catalyse the hydroxylation reaction of HIF-1 is prolyl hydroxylase domain proteins (PHDs). PHD inhibitors (PHIs) activate the HIF pathway by preventing degradation of HIF-αvia inhibiting PHDs. Osteogenesis and angiogenesis are tightly coupled during bone repair and regeneration. Numerous studies suggest that HIFs and their target gene, vascular endothelial growth factor (VEGF), are critical regulators of angiogenic-osteogenic coupling. In this brief perspective, we review current studies about the HIF pathway and its role in bone repair and regeneration, as well as the cellular and molecular mechanisms involved. Additionally, we briefly discuss the therapeutic manipulation of HIFs and VEGF in bone repair and bone tumours. This review will expand our knowledge of biology of HIFs, PHDs, PHD inhibitors, and bone regeneration, and it may also aid the design of novel therapies for accelerating bone repair and regeneration or inhibiting bone tumours.

scholarly journals Posttranscriptional regulation of T helper cell fate decisions

2018 ◽  
Vol 217 (8) ◽  
pp. 2615-2631 ◽  
Author(s):  
Kai P. Hoefig ◽  
Vigo Heissmeyer
Keyword(s):  
Signal Transduction ◽  
Transcription Factors ◽  
T Cell ◽  
Cell Fate ◽  
T Helper Cell ◽  
T Cell Subsets ◽  
Helper Cell ◽  
Regulation Of Transcription ◽  
T Helper ◽  
Cell Fate Decisions

T helper cell subsets orchestrate context- and pathogen-specific responses of the immune system. They mostly do so by secreting specific cytokines that attract or induce activation and differentiation of other immune or nonimmune cells. The differentiation of T helper 1 (Th1), Th2, T follicular helper, Th17, and induced regulatory T cell subsets from naive T cells depends on the activation of intracellular signal transduction cascades. These cascades originate from T cell receptor and costimulatory receptor engagement and also receive critical input from cytokine receptors that sample the cytokine milieu within secondary lymphoid organs. Signal transduction then leads to the expression of subset-specifying transcription factors that, in concert with other transcription factors, up-regulate downstream signature genes. Although regulation of transcription is important, recent research has shown that posttranscriptional and posttranslational regulation can critically shape or even determine the outcome of Th cell differentiation. In this review, we describe how specific microRNAs, long noncoding RNAs, RNA-binding proteins, and ubiquitin-modifying enzymes regulate their targets to skew cell fate decisions.

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