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 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.

Pluripotency transcription factors at the focus: the phase separation paradigm in stem cells

2021 ◽  
Author(s):  
Camila Oses ◽  
Martin Stortz ◽  
Paula Verneri ◽  
Alejandra Guberman ◽  
Valeria Levi
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Phase Separation ◽  
Cell Fate ◽  
Pluripotent Stem Cells ◽  
New Paradigm ◽  
Cell Fate Decisions ◽  
Key Players ◽  
New Ideas ◽  
Nuclear Processes

The transcription factors (TFs) OCT4, SOX2 and NANOG are key players of the gene regulatory network of pluripotent stem cells. Evidence accumulated in recent years shows that even small imbalances in the expression levels or relative concentrations of these TFs affect both, the maintenance of pluripotency and cell fate decisions. In addition, many components of the transcriptional machinery including RNA polymerases, cofactors and TFs such as those required for pluripotency, do not distribute homogeneously in the nucleus but concentrate in multiple foci influencing the delivery of these molecules to their DNA-targets. How cells control strict levels of available pluripotency TFs in this heterogeneous space and the biological role of these foci remain elusive. In recent years, a wealth of evidence led to propose that many of the nuclear compartments are formed through a liquid–liquid phase separation process. This new paradigm early penetrated the stem cells field since many key players of the pluripotency circuitry seem to phase-separate. Overall, the formation of liquid compartments may modulate the kinetics of biochemical reactions and consequently regulate many nuclear processes. Here, we review the state-of-the-art knowledge of compartmentalization in the cell nucleus and the relevance of this process for transcriptional regulation, particularly in pluripotent stem cells. We also highlight the recent advances and new ideas in the field showing how compartmentalization may affect pluripotency preservation and cell fate decisions.

scholarly journals The Roles of Chromatin Accessibility in Regulating the Candida albicans White-Opaque Phenotypic Switch

2021 ◽  
Vol 7 (1) ◽  
pp. 37
Author(s):  
Mohammad N. Qasim ◽  
Ashley Valle Arevalo ◽  
Clarissa J. Nobile ◽  
Aaron D. Hernday
Keyword(s):  
Candida Albicans ◽  
Cell Fate ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Phenotypic Switching ◽  
Phenotypic Switch ◽  
Chromatin Remodelers ◽  
Environmental Signals ◽  
Cell Fate Decisions ◽  
Simple Model System

Candida albicans, a diploid polymorphic fungus, has evolved a unique heritable epigenetic program that enables reversible phenotypic switching between two cell types, referred to as “white” and “opaque”. These cell types are established and maintained by distinct transcriptional programs that lead to differences in metabolic preferences, mating competencies, cellular morphologies, responses to environmental signals, interactions with the host innate immune system, and expression of approximately 20% of genes in the genome. Transcription factors (defined as sequence specific DNA-binding proteins) that regulate the establishment and heritable maintenance of the white and opaque cell types have been a primary focus of investigation in the field; however, other factors that impact chromatin accessibility, such as histone modifying enzymes, chromatin remodelers, and histone chaperone complexes, also modulate the dynamics of the white-opaque switch and have been much less studied to date. Overall, the white-opaque switch represents an attractive and relatively “simple” model system for understanding the logic and regulatory mechanisms by which heritable cell fate decisions are determined in higher eukaryotes. Here we review recent discoveries on the roles of chromatin accessibility in regulating the C. albicans white-opaque phenotypic switch.

Serrate and Notch specify cell fates in the heart field by suppressing cardiomyogenesis

Development ◽  
2000 ◽  
Vol 127 (17) ◽  
pp. 3865-3876
Author(s):  
M.S. Rones ◽  
K.A. McLaughlin ◽  
M. Raffin ◽  
M. Mercola
Keyword(s):  
Gene Expression ◽  
Notch Signaling ◽  
Cell Fate ◽  
Notch Pathway ◽  
Cell Types ◽  
Myocardial Cell ◽  
Dominant Negative ◽  
Cell Fates ◽  
Cell Fate Decisions ◽  
Heart Field

Notch signaling mediates numerous developmental cell fate decisions in organisms ranging from flies to humans, resulting in the generation of multiple cell types from equipotential precursors. In this paper, we present evidence that activation of Notch by its ligand Serrate apportions myogenic and non-myogenic cell fates within the early Xenopus heart field. The crescent-shaped field of heart mesoderm is specified initially as cardiomyogenic. While the ventral region of the field forms the myocardial tube, the dorsolateral portions lose myogenic potency and form the dorsal mesocardium and pericardial roof (Raffin, M., Leong, L. M., Rones, M. S., Sparrow, D., Mohun, T. and Mercola, M. (2000) Dev. Biol., 218, 326–340). The local interactions that establish or maintain the distinct myocardial and non-myocardial domains have never been described. Here we show that Xenopus Notch1 (Xotch) and Serrate1 are expressed in overlapping patterns in the early heart field. Conditional activation or inhibition of the Notch pathway with inducible dominant negative or active forms of the RBP-J/Suppressor of Hairless [Su(H)] transcription factor indicated that activation of Notch feeds back on Serrate1 gene expression to localize transcripts more dorsolaterally than those of Notch1, with overlap in the region of the developing mesocardium. Moreover, Notch pathway activation decreased myocardial gene expression and increased expression of a marker of the mesocardium and pericardial roof, whereas inhibition of Notch signaling had the opposite effect. Activation or inhibition of Notch also regulated contribution of individual cells to the myocardium. Importantly, expression of Nkx2. 5 and Gata4 remained largely unaffected, indicating that Notch signaling functions downstream of heart field specification. We conclude that Notch signaling through Su(H) suppresses cardiomyogenesis and that this activity is essential for the correct specification of myocardial and non-myocardial cell fates.

scholarly journals Do Neural Stem Cells Have a Choice? Heterogenic Outcome of Cell Fate Acquisition in Different Injury Models

2019 ◽  
Vol 20 (2) ◽  
pp. 455 ◽  
Author(s):  
Felix Beyer ◽  
Iria Samper Agrelo ◽  
Patrick Küry
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Cell Fate ◽  
Ex Vivo ◽  
Meta Analysis ◽  
Cell Types ◽  
Adult Brain ◽  
Repair Capacity ◽  
Cell Fate Decisions ◽  
Limiting Parameters

The adult mammalian central nervous system (CNS) is generally considered as repair restricted organ with limited capacities to regenerate lost cells and to successfully integrate them into damaged nerve tracts. Despite the presence of endogenous immature cell types that can be activated upon injury or in disease cell replacement generally remains insufficient, undirected, or lost cell types are not properly generated. This limitation also accounts for the myelin repair capacity that still constitutes the default regenerative activity at least in inflammatory demyelinating conditions. Ever since the discovery of endogenous neural stem cells (NSCs) residing within specific niches of the adult brain, as well as the description of procedures to either isolate and propagate or artificially induce NSCs from various origins ex vivo, the field has been rejuvenated. Various sources of NSCs have been investigated and applied in current neuropathological paradigms aiming at the replacement of lost cells and the restoration of functionality based on successful integration. Whereas directing and supporting stem cells residing in brain niches constitutes one possible approach many investigations addressed their potential upon transplantation. Given the heterogeneity of these studies related to the nature of grafted cells, the local CNS environment, and applied implantation procedures we here set out to review and compare their applied protocols in order to evaluate rate-limiting parameters. Based on our compilation, we conclude that in healthy CNS tissue region specific cues dominate cell fate decisions. However, although increasing evidence points to the capacity of transplanted NSCs to reflect the regenerative need of an injury environment, a still heterogenic picture emerges when analyzing transplantation outcomes in injury or disease models. These are likely due to methodological differences despite preserved injury environments. Based on this meta-analysis, we suggest future NSC transplantation experiments to be conducted in a more comparable way to previous studies and that subsequent analyses must emphasize regional heterogeneity such as accounting for differences in gray versus white matter.

scholarly journals Hypoxia-Inducible Factors 1α and 2α Regulate Trophoblast Differentiation

2005 ◽  
Vol 25 (23) ◽  
pp. 10479-10491 ◽  
Author(s):  
Karen D. Cowden Dahl ◽  
Benjamin H. Fryer ◽  
Fiona A. Mack ◽  
Veerle Compernolle ◽  
Emin Maltepe ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cell Types ◽  
Hypoxia Inducible Factors ◽  
Low Oxygen ◽  
Placental Development ◽  
Cell Fates ◽  
Trophoblast Stem Cells ◽  
Cell Fate Decisions ◽  
Hypoxic Environment ◽  
Life Threatening

ABSTRACT Placental development initially occurs in a low-oxygen (O2) or hypoxic environment. In this report we show that two hypoxia-inducible factors (HIFs), HIF1α and HIF2α, are essential for determining murine placental cell fates. HIF is a heterodimer composed of HIFα and HIFβ (ARNT) subunits. Placentas from Arnt − / − and Hif1α − / − Hif2α −/− embryos exhibit defective placental vascularization and aberrant cell fate adoption. HIF regulation of Mash2 promotes spongiotrophoblast differentiation, a prerequisite for trophoblast giant cell differentiation. In the absence of Arnt or Hifα, trophoblast stem cells fail to generate these cell types and become labyrinthine trophoblasts instead. Therefore, HIF mediates placental morphogenesis, angiogenesis, and cell fate decisions, demonstrating that O2 tension is a critical regulator of trophoblast lineage determination. This novel genetic approach provides new insights into the role of O2 tension in the development of life-threatening pregnancy-related diseases such as preeclampsia.

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.

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 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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