scholarly journals The Notch-mediated hyperplasia circuitry in Drosophila reveals a Src-JNK signaling axis

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Diana M Ho ◽  
SK Pallavi ◽  
Spyros Artavanis-Tsakonas
Keyword(s):  
Cell Fate ◽  
Tyrosine Kinases ◽  
Current Data ◽  
Jnk Pathway ◽  
Cell Fate Decisions ◽  
Genome Wide ◽  
A Genome ◽  
Wide Range ◽  
Signaling Axis ◽  
Transcriptional Changes

Notch signaling controls a wide range of cell fate decisions during development and disease via synergistic interactions with other signaling pathways. Here, through a genome-wide genetic screen in Drosophila, we uncover a highly complex Notch-dependent genetic circuitry that profoundly affects proliferation and consequently hyperplasia. We report a novel synergistic relationship between Notch and either of the non-receptor tyrosine kinases Src42A and Src64B to promote hyperplasia and tissue disorganization, which results in cell cycle perturbation, JAK/STAT signal activation, and differential regulation of Notch targets. Significantly, the JNK pathway is responsible for the majority of the phenotypes and transcriptional changes downstream of Notch-Src synergy. We previously reported that Notch-Mef2 also activates JNK, indicating that there are commonalities within the Notch-dependent proliferation circuitry; however, the current data indicate that Notch-Src accesses JNK in a significantly different fashion than Notch-Mef2.

scholarly journals KLF4 binding is involved in the organization and regulation of 3D enhancer networks during acquisition and maintenance of pluripotency

2018 ◽  
Author(s):  
Dafne Campigli Di Giammartino ◽  
Andreas Kloetgen ◽  
Alexander Polyzos ◽  
Yiyuan Liu ◽  
Daleum Kim ◽  
...  
Keyword(s):  
Cell Fate ◽  
Binding Sites ◽  
Target Gene ◽  
Embryonic Fibroblasts ◽  
Molecular Events ◽  
Genome Wide ◽  
A Genome ◽  
Integrative View ◽  
Transcriptional Changes ◽  
Complex Activities

SUMMARYCell fate transitions are accompanied by global transcriptional, epigenetic and topological changes driven by transcription factors (TFs), as is strikingly exemplified by reprogramming somatic cells to pluripotent stem cells (PSCs) via expression of OCT4, KLF4, SOX2 and cMYC. How TFs orchestrate the complex molecular changes around their target gene loci in a temporal manner remains incompletely understood. Here, using KLF4 as a paradigm, we provide the first TF-centric view of chromatin reorganization and its association to 3D enhancer rewiring and transcriptional changes of linked genes during reprogramming of mouse embryonic fibroblasts (MEFs) to PSCs. Inducible depletion of KLF factors in PSCs caused a genome-wide decrease in the connectivity of enhancers, while disruption of individual KLF4 binding sites from PSC-specific enhancers was sufficient to impair enhancer-promoter contacts and reduce expression of associated genes. Our study provides an integrative view of the complex activities of a lineage-specifying TF during a controlled cell fate transition and offers novel insights into the order and nature of molecular events that follow TF binding.

Gene Regulatory Networks Governing Hematopoietic Stem Cell Development and Identity

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-30-SCI-30 ◽  
Author(s):  
Tariq Enver
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Single Cells ◽  
Transcriptional Regulators ◽  
Gata Factor ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Genome Wide ◽  
A Genome ◽  
Custom Made

Abstract Abstract SCI-30 Several studies have addressed questions about transcriptional regulation within particular hematopoietic cell compartments. Few, however, have attempted to capture the transcriptional changes that occur during the dynamic transition from one compartment to another. We have profiled gene expression as multipotential progenitors underwent commitment and differentiation to two alternative lineages, focusing on the first 3 days of differentiation when the majority of decisions about cell fate are made. We have combined this with genome-wide identification of the targets of three key transcription factors before and after differentiation; GATA-2, usually associated with the stem/progenitor compartment; GATA-1 (erythroid); and PU.1 (myeloid). These data have been compiled into a custom-made queryable database, designed to be intuitive to use and to provide tools to interrogate the data on many levels. We used correlation analyses to associate transcription factor binding with particular modules of co-expressed genes, alongside detailed sequence analysis of bound regions. These approaches have informed our understanding of GATA factor switching, and highlighted novel roles for both GATA-2 and Pu.1 in erythroid cells. Overall, the data reveal greater degree of complexity in the interplay between these three factors in regulating hematopoiesis than has hitherto been described, and highlights the importance of a genome-wide approach to understanding complex regulatory systems. A significant challenge in the field is how to relate these types of population-based data to the action of transcriptional regulators within single cells where cell fate decisions ultimately are affected. As a step toward this, we have generated single cell profiles of gene expression for a limited set of transcriptional regulators in self-renewing and committed blood cells and used these data to build a stochastic computational model, which affords exploration of commitment scenarios in silico. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Role of Hypoxic Bone Marrow Microenvironment in Acute Myeloid Leukemia and Future Therapeutic Opportunities

2021 ◽  
Vol 22 (13) ◽  
pp. 6857
Author(s):  
Samantha Bruno ◽  
Manuela Mancini ◽  
Sara De Santis ◽  
Cecilia Monaldi ◽  
Michele Cavo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Cell Fate ◽  
Myeloid Leukemia ◽  
Hematologic Malignancy ◽  
Bone Marrow Microenvironment ◽  
Metabolic Adaptation ◽  
Cell Fate Decisions ◽  
Wide Range ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a hematologic malignancy caused by a wide range of alterations responsible for a high grade of heterogeneity among patients. Several studies have demonstrated that the hypoxic bone marrow microenvironment (BMM) plays a crucial role in AML pathogenesis and therapy response. This review article summarizes the current literature regarding the effects of the dynamic crosstalk between leukemic stem cells (LSCs) and hypoxic BMM. The interaction between LSCs and hypoxic BMM regulates fundamental cell fate decisions, including survival, self-renewal, and proliferation capacity as a consequence of genetic, transcriptional, and metabolic adaptation of LSCs mediated by hypoxia-inducible factors (HIFs). HIF-1α and some of their targets have been associated with poor prognosis in AML. It has been demonstrated that the hypoxic BMM creates a protective niche that mediates resistance to therapy. Therefore, we also highlight how hypoxia hallmarks might be targeted in the future to hit the leukemic population to improve AML patient outcomes.

Drosophila Gain-of-Function Mutant RTK Torso Triggers Ectopic Dpp and STAT Signaling

Genetics ◽  
2003 ◽  
Vol 164 (1) ◽  
pp. 247-258 ◽  
Author(s):  
Jinghong Li ◽  
Willis X Li
Keyword(s):  
Tyrosine Kinases ◽  
Target Genes ◽  
Tor Signaling ◽  
Gain Of Function ◽  
Essential Requirement ◽  
Downstream Target ◽  
Rtk Signaling ◽  
Genome Wide ◽  
A Genome ◽  
Genomic Regions

Abstract Overactivation of receptor tyrosine kinases (RTKs) has been linked to tumorigenesis. To understand how a hyperactivated RTK functions differently from wild-type RTK, we conducted a genome-wide systematic survey for genes that are required for signaling by a gain-of-function mutant Drosophila RTK Torso (Tor). We screened chromosomal deficiencies for suppression of a gain-of-function mutation tor (torGOF), which led to the identification of 26 genomic regions that, when in half dosage, suppressed the defects caused by torGOF. Testing of candidate genes in these regions revealed many genes known to be involved in Tor signaling (such as those encoding the Ras-MAPK cassette, adaptor and structural molecules of RTK signaling, and downstream target genes of Tor), confirming the specificity of this genetic screen. Importantly, this screen also identified components of the TGFβ (Dpp) and JAK/STAT pathways as being required for TorGOF signaling. Specifically, we found that reducing the dosage of thickveins (tkv), Mothers against dpp (Mad), or STAT92E (aka marelle), respectively, suppressed torGOF phenotypes. Furthermore, we demonstrate that in torGOF embryos, dpp is ectopically expressed and thus may contribute to the patterning defects. These results demonstrate an essential requirement of noncanonical signaling pathways for a persistently activated RTK to cause pathological defects in an organism.

scholarly journals A Genome-Wide RNA Interference Screen Identifies a Differential Role of the Mediator CDK8 Module Subunits for GATA/ RUNX-Activated Transcription in Drosophila

2010 ◽  
Vol 30 (11) ◽  
pp. 2837-2848 ◽  
Author(s):  
Vanessa Gobert ◽  
Dani Osman ◽  
Stéphanie Bras ◽  
Benoit Augé ◽  
Muriel Boube ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Rna Interference ◽  
Cell Fate ◽  
Gata Factor ◽  
Hematopoietic System ◽  
Crystal Cell ◽  
Genome Wide ◽  
A Genome

ABSTRACT Transcription factors of the RUNX and GATA families play key roles in the control of cell fate choice and differentiation, notably in the hematopoietic system. During Drosophila hematopoiesis, the RUNX factor Lozenge and the GATA factor Serpent cooperate to induce crystal cell differentiation. We used Serpent/Lozenge-activated transcription as a paradigm to identify modulators of GATA/RUNX activity by a genome-wide RNA interference screen in cultured Drosophila blood cells. Among the 129 factors identified, several belong to the Mediator complex. Mediator is organized in three modules plus a regulatory “CDK8 module,” composed of Med12, Med13, CycC, and Cdk8, which has long been thought to behave as a single functional entity. Interestingly, our data demonstrate that Med12 and Med13 but not CycC or Cdk8 are essential for Serpent/Lozenge-induced transactivation in cell culture. Furthermore, our in vivo analysis of crystal cell development show that, while the four CDK8 module subunits control the emergence and the proliferation of this lineage, only Med12 and Med13 regulate its differentiation. We thus propose that Med12/Med13 acts as a coactivator for Serpent/Lozenge during crystal cell differentiation independently of CycC/Cdk8. More generally, we suggest that the set of conserved factors identified herein may regulate GATA/RUNX activity in mammals.

The Genetics and Genomics of Asthma

2018 ◽  
Vol 19 (1) ◽  
pp. 223-246 ◽  
Author(s):  
Saffron A.G. Willis-Owen ◽  
William O.C. Cookson ◽  
Miriam F. Moffatt
Keyword(s):  
Sequence Variation ◽  
Human Microbiome ◽  
Technological Advances ◽  
Genome Wide ◽  
A Genome ◽  
Wide Range ◽  
Health And Disease ◽  
Wide Scale ◽  
Genetics And Genomics ◽  
The Individual

Asthma is a common, clinically heterogeneous disease with strong evidence of heritability. Progress in defining the genetic underpinnings of asthma, however, has been slow and hampered by issues of inconsistency. Recent advances in the tools available for analysis—assaying transcription, sequence variation, and epigenetic marks on a genome-wide scale—have substantially altered this landscape. Applications of such approaches are consistent with heterogeneity at the level of causation and specify patterns of commonality with a wide range of alternative disease traits. Looking beyond the individual as the unit of study, advances in technology have also fostered comprehensive analysis of the human microbiome and its varied roles in health and disease. In this article, we consider the implications of these technological advances for our current understanding of the genetics and genomics of asthma.

scholarly journals From conservation genetics to conservation genomics: a genome-wide assessment of blue whales ( Balaenoptera musculus ) in Australian feeding aggregations

2018 ◽  
Vol 5 (1) ◽  
pp. 170925 ◽  
Author(s):  
Catherine R. M. Attard ◽  
Luciano B. Beheregaray ◽  
Jonathan Sandoval-Castillo ◽  
K. Curt S. Jenner ◽  
Peter C. Gill ◽  
...  
Keyword(s):  
Population Structure ◽  
Adaptive Divergence ◽  
Balaenoptera Musculus ◽  
Blue Whale ◽  
Conservation Genomics ◽  
Next Generation Sequencing Technology ◽  
Genome Wide ◽  
A Genome ◽  
Wide Range ◽  
Blue Whales

Genetic datasets of tens of markers have been superseded through next-generation sequencing technology with genome-wide datasets of thousands of markers. Genomic datasets improve our power to detect low population structure and identify adaptive divergence. The increased population-level knowledge can inform the conservation management of endangered species, such as the blue whale ( Balaenoptera musculus ). In Australia, there are two known feeding aggregations of the pygmy blue whale ( B. m. brevicauda ) which have shown no evidence of genetic structure based on a small dataset of 10 microsatellites and mtDNA. Here, we develop and implement a high-resolution dataset of 8294 genome-wide filtered single nucleotide polymorphisms, the first of its kind for blue whales. We use these data to assess whether the Australian feeding aggregations constitute one population and to test for the first time whether there is adaptive divergence between the feeding aggregations. We found no evidence of neutral population structure and negligible evidence of adaptive divergence. We propose that individuals likely travel widely between feeding areas and to breeding areas, which would require them to be adapted to a wide range of environmental conditions. This has important implications for their conservation as this blue whale population is likely vulnerable to a range of anthropogenic threats both off Australia and elsewhere.

scholarly journals Theoretical study of the impact of adaptation on cell-fate heterogeneity and fractional killing

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Julien Hurbain ◽  
Darka Labavić ◽  
Quentin Thommen ◽  
Benjamin Pfeuty
Keyword(s):  
Cell Fate ◽  
Stochastic Dynamics ◽  
Biochemical Networks ◽  
Stochastic Bifurcation ◽  
Modeling Framework ◽  
Life And Death ◽  
Cell Fate Decisions ◽  
Wide Range ◽  
Adaptation Response ◽  
The Impact

Abstract Fractional killing illustrates the cell propensity to display a heterogeneous fate response over a wide range of stimuli. The interplay between the nonlinear and stochastic dynamics of biochemical networks plays a fundamental role in shaping this probabilistic response and in reconciling requirements for heterogeneity and controllability of cell-fate decisions. The stress-induced fate choice between life and death depends on an early adaptation response which may contribute to fractional killing by amplifying small differences between cells. To test this hypothesis, we consider a stochastic modeling framework suited for comprehensive sensitivity analysis of dose response curve through the computation of a fractionality index. Combining bifurcation analysis and Langevin simulation, we show that adaptation dynamics enhances noise-induced cell-fate heterogeneity by shifting from a saddle-node to a saddle-collision transition scenario. The generality of this result is further assessed by a computational analysis of a detailed regulatory network model of apoptosis initiation and by a theoretical analysis of stochastic bifurcation mechanisms. Overall, the present study identifies a cooperative interplay between stochastic, adaptation and decision intracellular processes that could promote cell-fate heterogeneity in many contexts.

scholarly journals RUNX1-ETO: Attacking the Epigenome for Genomic Instable Leukemia

2019 ◽  
Vol 20 (2) ◽  
pp. 350 ◽  
Author(s):  
Emiel van der Kouwe ◽  
Philipp Staber
Keyword(s):  
Fusion Protein ◽  
Target Genes ◽  
Underlying Mechanism ◽  
Current Data ◽  
Distal Enhancer ◽  
Dna Repair Mechanisms ◽  
Genome Wide ◽  
Wide Range ◽  
Repair Mechanisms ◽  
Comprehensive Picture

Oncogenic fusion protein RUNX1-ETO is the product of the t(8;21) translocation, responsible for the most common cytogenetic subtype of acute myeloid leukemia. RUNX1, a critical transcription factor in hematopoietic development, is fused with almost the entire ETO sequence with the ability to recruit a wide range of repressors. Past efforts in providing a comprehensive picture of the genome-wide localization and the target genes of RUNX1-ETO have been inconclusive in understanding the underlying mechanism by which it deregulates native RUNX1. In this review; we dissect the current data on the epigenetic impact of RUNX1 and RUNX1-ETO. Both share similarities however, in recent years, research focused on epigenetic factors to explain their differences. RUNX1-ETO impairs DNA repair mechanisms which compromises genomic stability and favors a mutator phenotype. Among an increasing pool of mutated factors, regulators of DNA methylation are frequently found in t(8;21) AML. Together with the alteration of both, histone markers and distal enhancer regulation, RUNX1-ETO might specifically disrupt normal chromatin structure. Epigenetic studies on the fusion protein uncovered new mechanisms contributing to leukemogenesis and hopefully will translate into clinical applications.

Genome-wide identification of SSR markers in the Brassica A genome and their utility in breeding

2016 ◽  
Vol 96 (5) ◽  
pp. 808-818 ◽  
Author(s):  
Neil Hobson ◽  
Habibur Rahman
Keyword(s):  
Genetic Diversity ◽  
Ssr Markers ◽  
Low Cost ◽  
Pak Choi ◽  
Genome Wide ◽  
A Genome ◽  
Wide Range ◽  
Genetic Pools ◽  
High Level ◽  
Simple Sequence

Simple sequence repeat (SSR) markers can be applied to genotyping projects at low cost with inexpensive equipment. The objective of this study was to develop SSR markers from the publically-available genome sequence of Brassica rapa and provide the physical position of these markers on the chromosomes for use in breeding and research. To assess the utility of these new markers, a subset of 60 markers were used to genotype 43 accessions of B. rapa. Fifty-five markers from the 10 chromosome scaffolds produced a total of 730 amplicons, which were then used to perform a phylogenetic analysis of the accessions, illustrating their utility in distinguishing between a wide range of germplasm. In agreement with similar studies of genetic diversity, our markers separated accessions into distinct genetic pools including Chinese cabbage, Chinese winter oilseed, European winter oilseed, Canadian spring oilseed, pak-choi, turnip, and yellow sarson. The results further illustrate the presence of a high level of genetic diversity in B. rapa, and demonstrate the potential of these SSR markers for use in breeding and research.

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