Distinct and overlapping gene regulatory networks in BMP- and HDAC-controlled cell fate determination in the embryonic forebrain

AbstractProper cell fate determination is largely orchestrated by complex gene regulatory networks centered around transcription factors. However, experimental elucidation of key transcription factors that drive cellular identity is currently often intractable. Here, we present ANANSE (ANalysis Algorithm for Networks Specified by Enhancers), a network-based method that exploits enhancer-encoded regulatory information to identify the key transcription factors in cell fate determination. As cell type-specific transcription factors predominantly bind to enhancers, we use regulatory networks based on enhancer properties to prioritize transcription factors. First, we predict genome-wide binding profiles of transcription factors in various cell types using enhancer activity and transcription factor binding motifs. Subsequently, applying these inferred binding profiles, we construct cell type-specific gene regulatory networks, and then predict key transcription factors controlling cell fate conversions using differential gene networks between cell types. This method outperforms existing approaches in correctly predicting major transcription factors previously identified to be sufficient for trans-differentiation. Finally, we apply ANANSE to define an atlas of key transcription factors in 18 normal human tissues. In conclusion, we present a ready-to-implement computational tool for efficient prediction of transcription factors in cell fate determination and to study transcription factor-mediated regulatory mechanisms. ANANSE is freely available at https://github.com/vanheeringen-lab/ANANSE.

Download Full-text

Complex Gene Regulatory Networks - from Structure to Biological Observables: Cell Fate Determination

10.1007/springerreference_60251 ◽

2011 ◽

Keyword(s):

Cell Fate ◽

Gene Regulatory Networks ◽

Regulatory Networks ◽

Cell Fate Determination ◽

Fate Determination ◽

Gene Regulatory

Download Full-text

Transient hysteresis and inherent stochasticity in gene regulatory networks

Nature Communications ◽

10.1038/s41467-019-12344-w ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 2

Author(s):

M. Pájaro ◽

I. Otero-Muras ◽

C. Vázquez ◽

A. A. Alonso

Keyword(s):

Cell Fate ◽

Gene Regulatory Networks ◽

Cellular Response ◽

Regulatory Networks ◽

Initial Conditions ◽

Quantitative Description ◽

Hysteresis Phenomenon ◽

Cell Fate Determination ◽

Fate Determination ◽

Gene Regulatory

Abstract Cell fate determination, the process through which cells commit to differentiated states is commonly mediated by gene regulatory motifs with mutually exclusive expression states. The classical deterministic picture for cell fate determination includes bistability and hysteresis, which enables the persistence of the acquired cellular state after withdrawal of the stimulus, ensuring a robust cellular response. However, stochasticity inherent to gene expression dynamics is not compatible with hysteresis, since the stationary solution of the governing Chemical Master Equation does not depend on the initial conditions. We provide a quantitative description of a transient hysteresis phenomenon reconciling experimental evidence of hysteretic behaviour in gene regulatory networks with inherent stochasticity: under sufficiently slow dynamics hysteresis is transient. We quantify this with an estimate of the convergence rate to the equilibrium and introduce a natural landscape capturing system’s evolution that, unlike traditional cell fate potential landscapes, is compatible with coexistence at the microscopic level.

Download Full-text

Engineering of a synthetic quadrastable gene network to approach Waddington landscape and cell fate determination

eLife ◽

10.7554/elife.23702 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 39

Author(s):

Fuqing Wu ◽

Ri-Qi Su ◽

Ying-Cheng Lai ◽

Xiao Wang

Keyword(s):

Cell Fate ◽

Regulatory Networks ◽

Cell Fate Determination ◽

Final States ◽

Cell Fates ◽

Fate Determination ◽

Cellular Decision Making ◽

Distinct Cell ◽

Model Predictions ◽

Gene Regulatory

The process of cell fate determination has been depicted intuitively as cells travelling and resting on a rugged landscape, which has been probed by various theoretical studies. However, few studies have experimentally demonstrated how underlying gene regulatory networks shape the landscape and hence orchestrate cellular decision-making in the presence of both signal and noise. Here we tested different topologies and verified a synthetic gene circuit with mutual inhibition and auto-activations to be quadrastable, which enables direct study of quadruple cell fate determination on an engineered landscape. We show that cells indeed gravitate towards local minima and signal inductions dictate cell fates through modulating the shape of the multistable landscape. Experiments, guided by model predictions, reveal that sequential inductions generate distinct cell fates by changing landscape in sequence and hence navigating cells to different final states. This work provides a synthetic biology framework to approach cell fate determination and suggests a landscape-based explanation of fixed induction sequences for targeted differentiation.

Download Full-text

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

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02259-z ◽

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.

Download Full-text

Gene Regulatory Networks Orchestrating B Cell Fate Specification, Commitment, and Differentiation

Molecular Analysis of B Lymphocyte Development and Activation - Current Topics in Microbiology and Immunology ◽

10.1007/3-540-26363-2_1 ◽

2005 ◽

pp. 1-14 ◽

Cited By ~ 5

Author(s):

K. L. Medina ◽

H. Singh

Keyword(s):

B Cell ◽

Cell Fate ◽

Gene Regulatory Networks ◽

Regulatory Networks ◽

Cell Fate Specification ◽

Fate Specification ◽

Gene Regulatory

Download Full-text

Multiple morphogens and rapid elongation promote segmental patterning during development

PLoS Computational Biology ◽

10.1371/journal.pcbi.1009077 ◽

2021 ◽

Vol 17 (6) ◽

pp. e1009077

Author(s):

Yuchi Qiu ◽

Lianna Fung ◽

Thomas F. Schilling ◽

Qing Nie

Keyword(s):

Cell Fate ◽

Gene Regulatory Networks ◽

Cell Sorting ◽

Short Range ◽

Regulatory Networks ◽

Neural Plate ◽

Convergent Extension ◽

Simultaneous Formation ◽

Gene Regulatory ◽

Rapid Elongation

The vertebrate hindbrain is segmented into rhombomeres (r) initially defined by distinct domains of gene expression. Previous studies have shown that noise-induced gene regulation and cell sorting are critical for the sharpening of rhombomere boundaries, which start out rough in the forming neural plate (NP) and sharpen over time. However, the mechanisms controlling simultaneous formation of multiple rhombomeres and accuracy in their sizes are unclear. We have developed a stochastic multiscale cell-based model that explicitly incorporates dynamic morphogenetic changes (i.e. convergent-extension of the NP), multiple morphogens, and gene regulatory networks to investigate the formation of rhombomeres and their corresponding boundaries in the zebrafish hindbrain. During pattern initiation, the short-range signal, fibroblast growth factor (FGF), works together with the longer-range morphogen, retinoic acid (RA), to specify all of these boundaries and maintain accurately sized segments with sharp boundaries. At later stages of patterning, we show a nonlinear change in the shape of rhombomeres with rapid left-right narrowing of the NP followed by slower dynamics. Rapid initial convergence improves boundary sharpness and segment size by regulating cell sorting and cell fate both independently and coordinately. Overall, multiple morphogens and tissue dynamics synergize to regulate the sizes and boundaries of multiple segments during development.

Download Full-text