scholarly journals The complex landscape of haematopoietic lineage commitments is encoded in the coarse-grained endogenous network

2021 ◽  
Vol 8 (11) ◽  
Author(s):  
Mengyao Wang ◽  
Junqiang Wang ◽  
Xingxing Zhang ◽  
Ruoshi Yuan
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Dynamic Models ◽  
Coarse Grained ◽  
State Transitions ◽  
Cell Fate Decisions ◽  
Differentiated Cells ◽  
Multipotent Progenitors ◽  
Ectopic Gene Expression ◽  
Complex Landscape

Haematopoietic lineage commitments are presented by a canonical roadmap in which haematopoietic stem cells or multipotent progenitors (MPPs) bifurcate into progenitors of more restricted lineages and ultimately mature to terminally differentiated cells. Although transcription factors playing significant roles in cell-fate commitments have been extensively studied, integrating such knowledge into the dynamic models to understand the underlying biological mechanism remains challenging. The hypothesis and modelling approach of the endogenous network has been developed previously and tested in various biological processes and is used in the present study of haematopoietic lineage commitments. The endogenous network is constructed based on the key transcription factors and their interactions that determine haematopoietic cell-fate decisions at each lineage branchpoint. We demonstrate that the process of haematopoietic lineage commitments can be reproduced from the landscape which orchestrates robust states of network dynamics and their transitions. Furthermore, some non-trivial characteristics are unveiled in the dynamical model. Our model also predicted previously under-represented regulatory interactions and heterogeneous MPP states by which distinct differentiation routes are intermediated. Moreover, network perturbations resulting in state transitions indicate the effects of ectopic gene expression on cellular reprogrammes. This study provides a predictive model to integrate experimental data and uncover the possible regulatory mechanism of haematopoietic lineage commitments.

scholarly journals Algorithmic Reconstruction of GBM Network Complexity

2021 ◽  
Author(s):  
Abicumaran Uthamacumaran ◽  
Morgan Craig
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Single Cell ◽  
Cell Fate ◽  
Data Science ◽  
Expression Patterns ◽  
State Transitions ◽  
Gene Expression Patterns ◽  
Cell Fate Decisions ◽  
Study Gene Expression

Glioblastoma (GBM) is a complex disease that is difficult to treat. Establishing the complex genetic interactions regulating cell fate decisions in GBM can help to shed light on disease aggressivity and improved treatments. Networks and data science offer novel approaches to study gene expression patterns from single-cell datasets, helping to distinguish genes associated with control of differentiation and thus aggressivity. Here, we applied a host of data theoretic techniques, including clustering algorithms, Waddington landscape reconstruction, trajectory inference algorithms, and network approaches, to compare gene expression patterns between pediatric and adult GBM, and those of adult GSCs (glioma-derived stem cells) to identify the key molecular regulators of the complex networks driving GBM/GSC and predict their cell fate dynamics. Using these tools, we identified critical genes and transcription factors coordinating cell state transitions from stem-like to mature GBM phenotypes, including eight transcription factors (OLIG1/2, TAZ, GATA2, FOXG1, SOX6, SATB2, YY1) and four signaling genes (ATL3, MTSS1, EMP1, and TPT1) as clinically targetable novel putative function interactions differentiating pediatric and adult GBMs from adult GSCs. Our study is among the first to provide strong evidence of the applicability of complex systems approaches for reverse-engineering gene networks from patient-derived single-cell datasets and inferring their complex dynamics, bolstering the search for new clinically- relevant targets in GBM.

scholarly journals Identification of transcription factors involved in the specification of photoreceptor subtypes

2021 ◽  
Author(s):  
Juan Angueyra ◽  
Vincent P Kunze ◽  
Laura K Patak ◽  
Hailey Kim ◽  
Katie Kindt ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Scientific Community ◽  
Screening Method ◽  
Cell Types ◽  
High Quality ◽  
Cell Fate Decisions ◽  
Key Players ◽  
Complex Landscape ◽  
Unique Cell

During development, retinal progenitors navigate a complex landscape of fate decisions that culminates with an array of unique cell types that are required for proper vision. Here, we aim to identify factors that are required for fate decisions in photoreceptors. These factors help create a diversity of photoreceptor subtypes that sustain vision in day and night, enable the detection of colors, of prey and predators, and other aspects of vision. To identify these factors, we generate a high-quality and deep transcriptomic profile of each photoreceptor subtype in zebrafish. From these profiles, we focus on transcription factors---key players in cell-fate decisions. We apply CRISPR-F0 screening as a versatile platform to explore the involvement of transcription factors in photoreceptor subtype-specification. We find that three differentially-expressed transcription factors (Foxq2, Tbx2a and Tbx2b) play unique roles in controlling the identity of photoreceptor subtypes within the retina. Our results provide novel insights into the function of these factors and how photoreceptors acquire their final identities. Furthermore, we have made our transcriptomic dataset openly available and easy to explore. This dataset and the screening method will be valuable to the scientific community and will enable the exploration of genes involved in many essential aspects of photoreceptor biology.

scholarly journals Controlling gene networks and cell fate with precision-targeted DNA-binding proteins and small-molecule-based genome readers

2014 ◽  
Vol 462 (3) ◽  
pp. 397-413 ◽  
Author(s):  
Asuka Eguchi ◽  
Garrett O. Lee ◽  
Fang Wan ◽  
Graham S. Erwin ◽  
Aseem Z. Ansari
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Cell Fate ◽  
Gene Networks ◽  
Regulatory Networks ◽  
Transcriptional Networks ◽  
Cell Fate Decisions ◽  
Differentiated Cells ◽  
Dna Binding Factors ◽  
Dna Binders

Transcription factors control the fate of a cell by regulating the expression of genes and regulatory networks. Recent successes in inducing pluripotency in terminally differentiated cells as well as directing differentiation with natural transcription factors has lent credence to the efforts that aim to direct cell fate with rationally designed transcription factors. Because DNA-binding factors are modular in design, they can be engineered to target specific genomic sequences and perform pre-programmed regulatory functions upon binding. Such precision-tailored factors can serve as molecular tools to reprogramme or differentiate cells in a targeted manner. Using different types of engineered DNA binders, both regulatory transcriptional controls of gene networks, as well as permanent alteration of genomic content, can be implemented to study cell fate decisions. In the present review, we describe the current state of the art in artificial transcription factor design and the exciting prospect of employing artificial DNA-binding factors to manipulate the transcriptional networks as well as epigenetic landscapes that govern cell fate.

scholarly journals Runx1 downregulates stem cell and megakaryocytic transcription programs that support niche interactions

Blood ◽  
2016 ◽  
Vol 127 (26) ◽  
pp. 3369-3381 ◽  
Author(s):  
Kira Behrens ◽  
Ioanna Triviai ◽  
Maike Schwieger ◽  
Nilgün Tekin ◽  
Malik Alawi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Cell Adhesion ◽  
Cell Fate ◽  
Bone Marrow Niche ◽  
Cell Fate Decisions ◽  
Multipotent Progenitors ◽  
Key Points

Key Points Runx1 is a key determinant of megakaryocyte cell-fate decisions in multipotent progenitors. Runx1 downregulates cell-adhesion factors that promote residency of stem cells and megakaryocytes in their bone marrow niche.

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.

Lineage Instructive Function of C/EBPα in Multipotent Hematopoietic Progenitor Cells Revealed in a Novel Cebpa-Cre Knock-in Model

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2458-2458
Author(s):  
Albert Wolfler ◽  
Astrid A Danen-van Oorschot ◽  
Jurgen Haanstra ◽  
Marijke Valkhof ◽  
Paulette van Strien ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Cell Fate ◽  
Cell Development ◽  
Hematopoietic Cell ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Multipotent Progenitors ◽  
Reported Data

Abstract Transcription factors control the lineage specification and differentiation of hematopoietic progenitor cells. They are expressed in a cell type-restricted pattern and activate lineage specific genetic programs. Recent studies have demonstrated that expression of GATA-1 or PU.1 in multipotent lin−Sca-1+c-Kit+ (LSK) cells specifies them to develop into myeloerythroid progenitors or lymphomyeloid progenitors, respectively. In contrast, C/EBPα, a transcription factor indispensable for the production of granulocytes and macrophages, is thought to predominantly act at a later stage of hematopoietic commitment, by governing the transition from common myeloid progenitors (CMPs) into granulocytic/monocytic progenitors (GMPs). To study whether C/EBPα may already exert a lineage instructive function at an earlier stage of hematopoietic cell development, i.e., at the level of multipotent LSK cells, we generated a knock-in mouse model expressing Cre recombinase under the regulation of the cebpa promoter and crossed C/EBPαcre/+ mice with R26 YFP reporter mice. This model faithfully demonstrates high levels of C/EBPα expression in myeloid cells and enabled us to trace cebpa-driven Cre/YFP expression in single LSK cells and their progeny by flow cytometry and colony cultures. On average cebpa-driven YFP expression was found in 17% (range 10–25%) of the total LSK fraction (n=12 mice). Within the CD150+CD48− CD34− subset of LSK cells, which contains the most primitive hematopoietic stem cells (HSC), 3–8% of the cells expressed YFP, indicating that cebpa is lowly expressed in bona fide HSC. This low level of expression appears insufficient for lineage determination, since the same levels of YFP expression (1–10%) were found in peripheral T and B cells. Within the CD34+ fraction of LSK cells, a population enriched for multipotent progenitors, 19% (range 14%–28%) of the cells expressed YFP. Identical distributions of YFP+ cells among the different LSK subsets were found in fetal livers of day 14.5 embryos, suggesting a comparable regulation of cebpa expression in fetal and adult cells. Similar to the reported data for GATA-1 and PU.1, cebpa-expressing LSK cells were predominantly found in the Sca-1low fraction. When cultured in a multilineage cytokine cocktail, YFP+ LSK cells gave predominantly rise to GM colonies (73% of all colonies; range 65–85%), whereas YFP− cells formed multiple types of colonies including mixed, megakaryocytic and erythroid colonies. The predominant outgrowth of YFP+ LSK cells to GM lineages was further supported in GM-CSF-supplemented colony assays, which gave rise to cloning efficiencies of 26% for YFP+ and 4% for YFP− LSK cells, respectively. In conclusion, our results show that C/EBPα starts to exert its instructive function towards GM cell development already within the LSK population, at the level of the multipotent progenitors. This has important ramifications for our understanding of the role of C/EBPα in early hematopoietic cell fate decisions.

Regulation of cell survival and proliferation by the FOXO (Forkhead box, class O) subfamily of Forkhead transcription factors

2003 ◽  
Vol 31 (1) ◽  
pp. 292-297 ◽  
Author(s):  
K.U. Birkenkamp ◽  
P.J. Coffer
Keyword(s):  
Transcription Factors ◽  
Cell Survival ◽  
Cell Fate ◽  
Nuclear Export ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Acute Lymphocytic Leukaemia ◽  
Cell Fate Decisions ◽  
Forkhead Transcription Factors ◽  
Forkhead Box

Recently, the FOXO (Forkhead box, class O) subfamily of Forkhead transcription factors has been identified as direct targets of phosphoinositide 3-kinase-mediated signal transduction. The AFX (acute-lymphocytic-leukaemia-1 fused gene from chromosome X), FKHR (Forkhead in rhabdomyosarcoma) and FKHR-L1 (FKHR-like 1) transcription factors are directly phosphorylated by protein kinase B, resulting in nuclear export and inhibition of transcription. This signalling pathway was first identified in the nematode worm Caenorhabditis elegans, where it has a role in regulation of the life span of the organism. Studies have shown that this evolutionarily conserved signalling module has a role in regulation of both cell-cycle progression and cell survival in higher eukaryotes. These effects are co-ordinated by FOXO-mediated induction of a variety of specific target genes that are only now beginning to be identified. Interestingly, FOXO transcription factors appear to be able to regulate transcription through both DNA-binding-dependent and -independent mechanisms. Our understanding of the regulation of FOXO activity, and defining specific transcriptional targets, may provide clues to the molecular mechanisms controlling cell fate decisions to divide, differentiate or die.

scholarly journals Balance between Id and E proteins regulates myeloid-versus-lymphoid lineage decisions

Blood ◽  
2009 ◽  
Vol 113 (5) ◽  
pp. 1016-1026 ◽  
Author(s):  
Shawn W. Cochrane ◽  
Ying Zhao ◽  
Robert S. Welner ◽  
Xiao-Hong Sun
Keyword(s):  
Transcription Factors ◽  
B Cell ◽  
Cell Fate ◽  
Intracellular Signaling ◽  
Specific Gene ◽  
B Cell Differentiation ◽  
E Proteins ◽  
Lymphoid Lineage ◽  
E Protein ◽  
Multipotent Progenitors

Abstract Hematopoiesis consists of a series of lineage decisions controlled by specific gene expression that is regulated by transcription factors and intracellular signaling events in response to environmental cues. Here, we demonstrate that the balance between E-protein transcription factors and their inhibitors, Id proteins, is important for the myeloid-versus-lymphoid fate choice. Using Id1-GFP knockin mice, we show that transcription of the Id1 gene begins to be up-regulated at the granulocyte-macrophage progenitor stage and continues throughout myelopoiesis. Id1 expression is also stimulated by cytokines favoring myeloid differentiation. Forced expression of Id1 in multipotent progenitors promotes myeloid development and suppresses B-cell formation. Conversely, enhancing E-protein activity by expressing a variant of E47 resistant to Id-mediated inhibition prevents the myeloid cell fate while driving B-cell differentiation from lymphoid-primed multipotent progenitors. Together, these results suggest a crucial function for E proteins in the myeloid-versus-lymphoid lineage decision.

scholarly journals Activity of the β-catenin phosphodestruction complex at cell–cell contacts is enhanced by cadherin-based adhesion

2009 ◽  
Vol 186 (2) ◽  
pp. 219-228 ◽  
Author(s):  
Meghan T. Maher ◽  
Annette S. Flozak ◽  
Adam M. Stocker ◽  
Anjen Chenn ◽  
Cara J. Gottardi
Keyword(s):  
Transcription Factors ◽  
Cell Adhesion ◽  
Cell Fate ◽  
Cell Contacts ◽  
Cell Fate Decisions ◽  
T Cell Factor ◽  
Protein Levels ◽  
Gsk 3Β ◽  
Canonical Wnt ◽  
Cell Cell

It is well established that cadherin protein levels impact canonical Wnt signaling through binding and sequestering β-catenin (β-cat) from T-cell factor family transcription factors. Whether changes in intercellular adhesion can affect β-cat signaling and the mechanism through which this occurs has remained unresolved. We show that axin, APC2, GSK-3β and N-terminally phosphorylated forms of β-cat can localize to cell–cell contacts in a complex that is molecularly distinct from the cadherin–catenin adhesive complex. Nonetheless, cadherins can promote the N-terminal phosphorylation of β-cat, and cell–cell adhesion increases the turnover of cytosolic β-cat. Together, these data suggest that cadherin-based cell–cell adhesion limits Wnt signals by promoting the activity of a junction-localized β-cat phosphodestruction complex, which may be relevant to tissue morphogenesis and cell fate decisions during development.

Epigenetic regulation in stem cell development, cell fate conversion, and reprogramming

2015 ◽  
Vol 6 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Kazuyuki Ohbo ◽  
Shin-ichi Tomizawa
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Transcription Factors ◽  
Cell Fate ◽  
Cell Lines ◽  
Cell Fate Decisions ◽  
Micro Rnas ◽  
Stem Cell Lines ◽  
Cell Fate Conversion

AbstractStem cells are identified classically by an in vivo transplantation assay plus additional characterization, such as marker analysis, linage-tracing and in vitro/ex vivo differentiation assays. Stem cell lines have been derived, in vitro, from adult tissues, the inner cell mass (ICM), epiblast, and male germ stem cells, providing intriguing insight into stem cell biology, plasticity, heterogeneity, metastable state, and the pivotal point at which stem cells irreversibly differentiate to non-stem cells. During the past decade, strategies for manipulating cell fate have revolutionized our understanding about the basic concept of cell differentiation: stem cell lines can be established by introducing transcription factors, as with the case for iPSCs, revealing some of the molecular interplay of key factors during the course of phenotypic changes. In addition to de-differentiation approaches for establishing stem cells, another method has been developed whereby induced expression of certain transcription factors and/or micro RNAs artificially converts differentiated cells from one committed lineage to another; notably, these cells need not transit through a stem/progenitor state. The molecular cues guiding such cell fate conversion and reprogramming remain largely unknown. As differentiation and de-differentiation are directly linked to epigenetic changes, we overview cell fate decisions, and associated gene and epigenetic regulations.

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