scholarly journals Cell fate-decision as high-dimensional critical state transition

2016 ◽  
Author(s):  
Mitra Mojtahedi ◽  
Alexander Skupin ◽  
Joseph Zhou ◽  
Ivan G. Castaño ◽  
Rebecca Y. Y. Leong-Quong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Progenitor Cells ◽  
Cell Fate ◽  
Critical State ◽  
State Transition ◽  
High Dimensional ◽  
Critical Transitions ◽  
Formal Tool ◽  
Multipotent Progenitor Cells ◽  
Fate Decision

AbstractCell fate choice and commitment of multipotent progenitor cells to a differentiated lineage requires broad changes of their gene expression profile. However, how progenitor cells overcome the stability of their robust gene expression configuration (attractor) and exit their state remains elusive. Here we show that commitment of blood progenitor cells to the erythroid or the myeloid lineage is preceded by the destabilization of their high-dimensional attractor state and that cells undergo a critical state transition. Single-cell resolution analysis of gene expression in populations of differentiating cells affords a new quantitative index for predicting critical transitions in a high-dimensional state space: decrease of correlation between cells with concomitant increase of correlation between genes as cells approach a tipping point. The detection of “rebellious cells” which enter the fate opposite to the one intended corroborates the model of preceding destabilization of the progenitor state. Thus, “early-warning signals” associated with critical transitions can be detected in statistical ensembles of high-dimensional systems, offering a formal tool for analyzing single-cell’s molecular profiles that goes beyond computational pattern recognition but is based on dynamical systems theory and can predict impending major shifts in cell populations in development and disease.

scholarly journals Cell Fate Decision as High-Dimensional Critical State Transition

PLoS Biology ◽  
2016 ◽  
Vol 14 (12) ◽  
pp. e2000640 ◽  
Author(s):  
Mitra Mojtahedi ◽  
Alexander Skupin ◽  
Joseph Zhou ◽  
Ivan G. Castaño ◽  
Rebecca Y. Y. Leong-Quong ◽  
...  
Keyword(s):  
Cell Fate ◽  
Critical State ◽  
State Transition ◽  
High Dimensional ◽  
Cell Fate Decision ◽  
Fate Decision

scholarly journals Cell population structure prior to bifurcation predicts efficiency of directed differentiation in human induced pluripotent cells

2017 ◽  
Vol 114 (9) ◽  
pp. 2271-2276 ◽  
Author(s):  
Rhishikesh Bargaje ◽  
Kalliopi Trachana ◽  
Martin N. Shelton ◽  
Christopher S. McGinnis ◽  
Joseph X. Zhou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Population Structure ◽  
Cell Fate ◽  
Cell Population ◽  
Critical State ◽  
State Transition ◽  
Tipping Point ◽  
Patient Specific ◽  
Cell Populations ◽  
Induced Pluripotent

Steering the differentiation of induced pluripotent stem cells (iPSCs) toward specific cell types is crucial for patient-specific disease modeling and drug testing. This effort requires the capacity to predict and control when and how multipotent progenitor cells commit to the desired cell fate. Cell fate commitment represents a critical state transition or “tipping point” at which complex systems undergo a sudden qualitative shift. To characterize such transitions during iPSC to cardiomyocyte differentiation, we analyzed the gene expression patterns of 96 developmental genes at single-cell resolution. We identified a bifurcation event early in the trajectory when a primitive streak-like cell population segregated into the mesodermal and endodermal lineages. Before this branching point, we could detect the signature of an imminent critical transition: increase in cell heterogeneity and coordination of gene expression. Correlation analysis of gene expression profiles at the tipping point indicates transcription factors that drive the state transition toward each alternative cell fate and their relationships with specific phenotypic readouts. The latter helps us to facilitate small molecule screening for differentiation efficiency. To this end, we set up an analysis of cell population structure at the tipping point after systematic variation of the protocol to bias the differentiation toward mesodermal or endodermal cell lineage. We were able to predict the proportion of cardiomyocytes many days before cells manifest the differentiated phenotype. The analysis of cell populations undergoing a critical state transition thus affords a tool to forecast cell fate outcomes and can be used to optimize differentiation protocols to obtain desired cell populations.

scholarly journals GATA-targeted compounds modulate cardiac subtype cell differentiation in dual reporter stem cell line

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mika J. Välimäki ◽  
Robert S. Leigh ◽  
Sini M. Kinnunen ◽  
Alexander R. March ◽  
Ana Hernández de Sande ◽  
...  
Keyword(s):  
Gene Expression ◽  
Progenitor Cells ◽  
Cell Fate ◽  
Reporter Gene ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Cell Fate Decisions ◽  
Dual Reporter ◽  
Gene Regulatory ◽  
Reporter Gene Assays

AbstractBackgroundPharmacological modulation of cell fate decisions and developmental gene regulatory networks holds promise for the treatment of heart failure. Compounds that target tissue-specific transcription factors could overcome non-specific effects of small molecules and lead to the regeneration of heart muscle following myocardial infarction. Due to cellular heterogeneity in the heart, the activation of gene programs representing specific atrial and ventricular cardiomyocyte subtypes would be highly desirable. Chemical compounds that modulate atrial and ventricular cell fate could be used to improve subtype-specific differentiation of endogenous or exogenously delivered progenitor cells in order to promote cardiac regeneration.MethodsTranscription factor GATA4-targeted compounds that have previously shown in vivo efficacy in cardiac injury models were tested for stage-specific activation of atrial and ventricular reporter genes in differentiating pluripotent stem cells using a dual reporter assay. Chemically induced gene expression changes were characterized by qRT-PCR, global run-on sequencing (GRO-seq) and immunoblotting, and the network of cooperative proteins of GATA4 and NKX2-5 were further explored by the examination of the GATA4 and NKX2-5 interactome by BioID. Reporter gene assays were conducted to examine combinatorial effects of GATA-targeted compounds and bromodomain and extraterminal domain (BET) inhibition on chamber-specific gene expression.ResultsGATA4-targeted compounds 3i-1000 and 3i-1103 were identified as differential modulators of atrial and ventricular gene expression. More detailed structure-function analysis revealed a distinct subclass of GATA4/NKX2-5 inhibitory compounds with an acetyl lysine-like domain that contributed to ventricular cells (%Myl2-eGFP+). Additionally, BioID analysis indicated broad interaction between GATA4 and BET family of proteins, such as BRD4. This indicated the involvement of epigenetic modulators in the regulation of GATA-dependent transcription. In this line, reporter gene assays with combinatorial treatment of 3i-1000 and the BET bromodomain inhibitor (+)-JQ1 demonstrated the cooperative role of GATA4 and BRD4 in the modulation of chamber-specific cardiac gene expression.ConclusionsCollectively, these results indicate the potential for therapeutic alteration of cell fate decisions and pathological gene regulatory networks by GATA4-targeted compounds modulating chamber-specific transcriptional programs in multipotent cardiac progenitor cells and cardiomyocytes. The compound scaffolds described within this study could be used to develop regenerative strategies for myocardial regeneration.

scholarly journals Notch1 regulates the fate of cardiac progenitor cells

2008 ◽  
Vol 105 (40) ◽  
pp. 15529-15534 ◽  
Author(s):  
Alessandro Boni ◽  
Konrad Urbanek ◽  
Angelo Nascimbene ◽  
Toru Hosoda ◽  
Hanqiao Zheng ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Cell Fate ◽  
Nuclear Translocation ◽  
Notch Receptor ◽  
Cardiac Progenitor Cells ◽  
Supporting Cells ◽  
Multiple Organs ◽  
Myocyte Differentiation ◽  
Fate Decision

The Notch receptor mediates cell fate decision in multiple organs. In the current work we tested the hypothesis that Nkx2.5 is a target gene of Notch1 and raised the possibility that Notch1 regulates myocyte commitment in the adult heart. Cardiac progenitor cells (CPCs) in the niches express Notch1 receptor, and the supporting cells exhibit the Notch ligand Jagged1. The nuclear translocation of Notch1 intracellular domain (N1ICD) up-regulates Nkx2.5 in CPCs and promotes the formation of cycling myocytes in vitro. N1ICD and RBP-Jk form a protein complex, which in turn binds to the Nkx2.5 promoter initiating transcription and myocyte differentiation. In contrast, transcription factors of vascular cells are down-regulated by Jagged1 activation of the Notch1 pathway. Importantly, inhibition of Notch1 in infarcted mice impairs the commitment of resident CPCs to the myocyte lineage opposing cardiomyogenesis. These observations indicate that Notch1 favors the early specification of CPCs to the myocyte phenotype but maintains the newly formed cells in a highly proliferative state. Dividing Nkx2.5-positive myocytes correspond to transit amplifying cells, which condition the replicative capacity of the heart. In conclusion, Notch1 may have critical implications in the control of heart homeostasis and its adaptation to pathologic states.

scholarly journals Integrated time-lapse and single-cell transcription studies highlight the variable and dynamic nature of human hematopoietic cell fate commitment

2017 ◽  
Author(s):  
Alice Moussy ◽  
Jérémie Cosette ◽  
Romuald Parmentier ◽  
Cindy da Silva ◽  
Guillaume Corre ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Single Cell ◽  
Cell Fate ◽  
Morphological Changes ◽  
Gene Expression Pattern ◽  
Time Lapse ◽  
Dynamic Nature ◽  
Transcriptional Changes ◽  
Fate Decision

AbstractIndividual cells take lineage commitment decisions in a way that is not necessarily uniform. We address this issue by characterizing transcriptional changes in cord blood derived CD34+ cells at the single-cell level and integrating data with cell division history and morphological changes determined by time-lapse microscopy. We show, that major transcriptional changes leading to a multilineage-primed gene expression state occur very rapidly during the first cell cycle. One of the two stable lineage-primed patterns emerges gradually in each cell with variable timing. Some cells reach a stable morphology and molecular phenotype by the end of the first cell cycle and transmit it clonally. Others fluctuate between the two phenotypes over several cell cycles. Our analysis highlights the dynamic nature and variable timing of cell fate commitment in hematopoietic cells, links the gene expression pattern to cell morphology and identifies a new category of cells with fluctuating phenotypic characteristics, demonstrating the complexity of the fate decision process, away from a simple binary switch between two options as it is usually envisioned.

scholarly journals Differential chromatin accessibility in developing projection neurons is correlated with transcriptional regulation of cell fate

2019 ◽  
Author(s):  
Whitney E. Heavner ◽  
Shaoyi Ji ◽  
James H. Notwell ◽  
Ethan S. Dyer ◽  
Alex M. Tseng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Progenitor Cells ◽  
Cell Fate ◽  
Expression Profiles ◽  
Chromatin Accessibility ◽  
Transcriptional Networks ◽  
Projection Neurons ◽  
Cortical Projection ◽  
Functional Features

AbstractWe are only just beginning to catalog the vast diversity of cell types in the cerebral cortex. Such categorization is a first step toward understanding how diversification relates to function. All cortical projection neurons arise from a uniform pool of progenitor cells that lines the ventricles of the forebrain. It is still unclear how these progenitor cells generate the more than fifty unique types of mature cortical projection neurons defined by their distinct gene expression profiles. Here we compare gene expression and chromatin accessibility of two subclasses of projection neurons with divergent morphological and functional features as they develop in the mouse brain between embryonic day 13 and postnatal day 5 in order to identify transcriptional networks that diversity neuron cell fate. We find groups of transcription factors whose expression is correlated with chromatin accessibility, transcription factor binding motifs, and lncRNAs that define each subclass and validate the function of a family of novel candidate genes in vitro. Our multidimensional approach reveals that subclass-specific chromatin accessibility is significantly correlated with gene expression, providing a resource for generating new specific genetic drivers and revealing regions of the genome that are particularly susceptible to harmful genetic mutations by virtue of their correlation with important developmental genes.

Sign in / Sign up

Export Citation Format

Share Document