More than just Stem Cells: Functional Roles of the Transcription Factor Sox2 in Differentiated Glia and Neurons

The Sox2 transcription factor, encoded by a gene conserved in animal evolution, has become widely known because of its functional relevance for stem cells. In the developing nervous system, Sox2 is active in neural stem cells, and important for their self-renewal; differentiation to neurons and glia normally involves Sox2 downregulation. Recent evidence, however, identified specific types of fully differentiated neurons and glia that retain high Sox2 expression, and critically require Sox2 function, as revealed by functional studies in mouse and in other animals. Sox2 was found to control fundamental aspects of the biology of these cells, such as the development of correct neuronal connectivity. Sox2 downstream target genes identified within these cell types provide molecular mechanisms for cell-type-specific Sox2 neuronal and glial functions. SOX2 mutations in humans lead to a spectrum of nervous system defects, involving vision, movement control, and cognition; the identification of neurons and glia requiring Sox2 function, and the investigation of Sox2 roles and molecular targets within them, represents a novel perspective for the understanding of the pathogenesis of these defects.

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A novel fibroblast growth factor gene expressed in the developing nervous system is a downstream target of the chimeric homeodomain oncoprotein E2A-Pbx1

Development ◽

10.1242/dev.124.17.3221 ◽

1997 ◽

Vol 124 (17) ◽

pp. 3221-3232 ◽

Cited By ~ 10

Author(s):

J.R. McWhirter ◽

M. Goulding ◽

J.A. Weiner ◽

J. Chun ◽

C. Murre

Keyword(s):

Nervous System ◽

Transcription Factor ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Target Genes ◽

Representational Difference Analysis ◽

Bhlh Transcription Factor ◽

Fibroblast Growth ◽

Downstream Target ◽

Developing Nervous System

Pbx1 is a homeodomain transcription factor that has the ability to form heterodimers with homeodomain proteins encoded by the homeotic selector (Hox) gene complexes and increase their DNA-binding affinity and specificity. A current hypothesis proposes that interactions with Pbx1 are necessary for Hox proteins to regulate downstream target genes that in turn control growth, differentiation and morphogenesis during development. In pre B cell leukemias containing the t(1;19) chromosome translocation, Pbx1 is converted into a strong transactivator by fusion to the activation domain of the bHLH transcription factor E2A. The E2A-Pbx1 fusion protein should therefore activate transcription of genes normally regulated by Pbx1. We have used the subtractive process of representational difference analysis to identify targets of E2A-Pbx1. We show that E2A-Pbx1 can directly activate transcription of a novel member of the fibroblast growth factor family of intercellular signalling molecules, FGF-15. The FGF-15 gene is expressed in a regionally restricted pattern in the developing nervous system, suggesting that FGF-15 may play an important role in regulating cell division and patterning within specific regions of the embryonic brain, spinal cord and sensory organs.

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Bioinformatic Analysis of Transcriptional Regulation by Nur77 in Central Nervous System and Immune System

10.21203/rs.3.rs-505939/v1 ◽

2021 ◽

Author(s):

Montserrat Olivares Costa ◽

Fernando Faunes ◽

María Estela Andrés

Keyword(s):

Stem Cells ◽

Central Nervous System ◽

Nervous System ◽

Transcription Factor ◽

Immune Cells ◽

Binding Sites ◽

Target Genes ◽

Bioinformatic Analysis ◽

Neuronal Stem Cells

Abstract ObjectiveThe objectives of this work were to find genes regulated by Nur77 in neurons and to evaluate the possible common role of this transcription factor in neurons and lymphatic cells using published experimentally generated databases of ChIP-Seq and a microarray. We also characterized Nur77 binding throughout the genome. ResultsWe identified 113 Nur77 target genes in neuronal stem cells and 116 in neuronal cells. Cell adhesion and anchoring processes emerged as regulated by Nur77 in neurons and lymphatic cells. We found 9 common genes regulated by Nur77. Finally, we described a significant distribution of Nur77 binding sites in strong enhancers and active promoters. This work is a first step to understand the role of Nur77 and its common targets in neurons and immune cells.

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Roles of p53 in Various Biological Aspects of Hematopoietic Stem Cells

Journal of Biomedicine and Biotechnology ◽

10.1155/2012/903435 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 10

Author(s):

Takenobu Nii ◽

Tomotoshi Marumoto ◽

Kenzaburo Tani

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Molecular Mechanisms ◽

Target Genes ◽

Cell Types ◽

Cell Integrity ◽

Hematopoietic Stem ◽

Cycle Arrest ◽

Successful Transplantation ◽

Cellular Stresses

Hematopoietic stem cells (HSCs) have the capacity to self-renew as well as to differentiate into all blood cell types, and they can reconstitute hematopoiesis in recipients with bone marrow ablation. In addition, transplantation therapy using HSCs is widely performed for the treatment of various incurable diseases such as hematopoietic malignancies and congenital immunodeficiency disorders. For the safe and successful transplantation of HSCs, their genetic and epigenetic integrities need to be maintained properly. Therefore, understanding the molecular mechanisms that respond to various cellular stresses in HSCs is important. The tumor suppressor protein, p53, has been shown to play critical roles in maintenance of “cell integrity” under stress conditions by controlling its target genes that regulate cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. In this paper, we summarize recent reports that describe various biological functions of HSCs and discuss the roles of p53 associated with them.

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The emerging roles of Oct4 in tumor-initiating cells

AJP Cell Physiology ◽

10.1152/ajpcell.00212.2015 ◽

2015 ◽

Vol 309 (11) ◽

pp. C709-C718 ◽

Cited By ~ 52

Author(s):

Ying-Jie Wang ◽

Meenhard Herlyn

Keyword(s):

Stem Cells ◽

Transcription Factor ◽

Pluripotent Stem Cells ◽

Molecular Mechanisms ◽

Target Genes ◽

Large Body ◽

Tumor Initiating Cells ◽

Self Renewal ◽

Mesenchymal Transition ◽

Main Challenge

Octamer-binding transcription factor 4 (Oct4), a homeodomain transcription factor, is well established as a master factor controlling the self-renewal and pluripotency of pluripotent stem cells. Also, a large body of research has documented the detection of Oct4 in tumor cells and tissues and has indicated its enrichment in a subpopulation of undifferentiated tumor-initiating cells (TICs) that critically account for tumor initiation, metastasis, and resistance to anticancer therapies. There is circumstantial evidence for low-level expression of Oct4 in cancer cells and TICs, and the participation of Oct4 in various TIC functions such as its self-renewal and survival, epithelial-mesenchymal transition (EMT) and metastasis, and drug resistance development is implicated from considerable Oct4 knockdown and overexpression-based studies. In a few studies, efforts have been made to identify Oct4 target genes in TICs of different sources. Based on such information, Oct4 in TICs appears to act via mechanisms quite distinct from those in pluripotent stem cells, and a main challenge for future studies is to unravel the molecular mechanisms of action of Oct4, particularly to address the question on how such low levels of Oct4 may exert its functions in TICs. Acquiring cells from their native microenvironment that are of high enough quantity and purity is the key to reliably analyze Oct4 functions and its target genes in TICs, and the information gained may greatly facilitate targeting and eradicating those cells.

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Chromatin accessibility changes betweenArabidopsisstem cells and mesophyll cells illuminate cell type-specific transcription factor networks

10.1101/213900 ◽

2017 ◽

Cited By ~ 1

Author(s):

Paja Sijacic ◽

Marko Bajic ◽

Elizabeth C. McKinney ◽

Richard B. Meagher ◽

Roger B. Deal

Keyword(s):

Stem Cells ◽

Transcription Factor ◽

Regulatory Networks ◽

Target Genes ◽

Cell Types ◽

Chromatin Accessibility ◽

Cell Type ◽

Mesophyll Cells ◽

Leaf Mesophyll ◽

Cell Type Specific

AbstractBackgroundCell differentiation is driven by changes in transcription factor (TF) activity and subsequent alterations in transcription. To study this process, differences in TF binding between cell types can be deduced by methods that probe chromatin accessibility. We used cell type-specific nuclei purification followed by the Assay for Transposase Accessible Chromatin (ATAC-seq) to delineate differences in chromatin accessibility and TF regulatory networks between stem cells of the shoot apical meristem (SAM) and differentiated leaf mesophyll cells ofArabidopsis thaliana.ResultsChromatin accessibility profiles of SAM stem cells and leaf mesophyll cells were highly similar at a qualitative level, yet thousands of regions of quantitatively different chromatin accessibility were also identified. We found that chromatin regions preferentially accessible in mesophyll cells tended to also be substantially accessible in the stem cells as compared to the genome-wide average, whereas the converse was not true. Analysis of genomic regions preferentially accessible in each cell type identified hundreds of overrepresented TF binding motifs, highlighting a set of TFs that are likely important for each cell type. Among these, we found evidence for extensive co-regulation of target genes by multiple TFs that are preferentially expressed in one cell type or the other. For example, a set of zinc-finger TFs appear to control a suite of growth-and development-related genes specifically in stem cells, while another TF set co-regulates genes involved in light responses and photosynthesis specifically in mesophyll cells. Interestingly, the TFs within both of these sets also show evidence of extensively co-regulating each other.ConclusionsQuantitative analysis of chromatin accessibility differences between stem cells and differentiated mesophyll cells allowed us to identify TF regulatory networks and downstream target genes that are likely to be functionally important in each cell type. Our findings that mesophyll cell-enriched accessible sites tend to already be substantially accessible in stem cells, but not vice versa, suggests that widespread regulatory element accessibility may be important for the developmental plasticity of stem cells. This work also demonstrates the utility of cell type-specific chromatin accessibility profiling in quickly developing testable models of regulatory control differences between cell types.

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MicroRNAs and Stem-like Properties: The Complex Regulation Underlying Stemness Maintenance and Cancer Development

Biomolecules ◽

10.3390/biom11081074 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1074

Author(s):

Giuseppina Divisato ◽

Silvia Piscitelli ◽

Mariantonietta Elia ◽

Emanuela Cascone ◽

Silvia Parisi

Keyword(s):

Stem Cells ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Embryonic Stem ◽

Cell Types ◽

Cancer Development ◽

Special Focus ◽

Self Renewal ◽

Mesenchymal Transition ◽

Different Cell Types

Embryonic stem cells (ESCs) have the extraordinary properties to indefinitely proliferate and self-renew in culture to produce different cell progeny through differentiation. This latter process recapitulates embryonic development and requires rounds of the epithelial–mesenchymal transition (EMT). EMT is characterized by the loss of the epithelial features and the acquisition of the typical phenotype of the mesenchymal cells. In pathological conditions, EMT can confer stemness or stem-like phenotypes, playing a role in the tumorigenic process. Cancer stem cells (CSCs) represent a subpopulation, found in the tumor tissues, with stem-like properties such as uncontrolled proliferation, self-renewal, and ability to differentiate into different cell types. ESCs and CSCs share numerous features (pluripotency, self-renewal, expression of stemness genes, and acquisition of epithelial–mesenchymal features), and most of them are under the control of microRNAs (miRNAs). These small molecules have relevant roles during both embryogenesis and cancer development. The aim of this review was to recapitulate molecular mechanisms shared by ESCs and CSCs, with a special focus on the recently identified classes of microRNAs (noncanonical miRNAs, mirtrons, isomiRs, and competitive endogenous miRNAs) and their complex functions during embryogenesis and cancer development.

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The role of m6A modification in the biological functions and diseases

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-020-00450-x ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Xiulin Jiang ◽

Baiyang Liu ◽

Zhi Nie ◽

Lincan Duan ◽

Qiuxia Xiong ◽

...

Keyword(s):

Cancer Progression ◽

Molecular Mechanisms ◽

Target Genes ◽

Rna Modification ◽

Biological Functions ◽

Rna Methylation ◽

Downstream Target ◽

Different Types ◽

M6a Rna Methylation

AbstractN6-methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher eukaryotic cells. m6A modification is modified by the m6A methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429, and, removed by the demethylases, or erasers, including FTO and ALKBH5. It is recognized by m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1, also known as “readers”. Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions, especially in the initiation and progression of different types of human cancers. In this review, we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic, central nervous and reproductive systems. We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation, its regulators and downstream target genes, during cancer progression in above systems. We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future.

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First blood: the endothelial origins of hematopoietic progenitors

Angiogenesis ◽

10.1007/s10456-021-09783-9 ◽

2021 ◽

Author(s):

Giovanni Canu ◽

Christiana Ruhrberg

Keyword(s):

Stem Cells ◽

Molecular Mechanisms ◽

Vascular Endothelial Cells ◽

Fetal Liver ◽

Cell Types ◽

Yolk Sac ◽

Vascular Endothelial ◽

Hematopoietic Stem ◽

Close Proximity ◽

Clinical Interest

AbstractHematopoiesis in vertebrate embryos occurs in temporally and spatially overlapping waves in close proximity to blood vascular endothelial cells. Initially, yolk sac hematopoiesis produces primitive erythrocytes, megakaryocytes, and macrophages. Thereafter, sequential waves of definitive hematopoiesis arise from yolk sac and intraembryonic hemogenic endothelia through an endothelial-to-hematopoietic transition (EHT). During EHT, the endothelial and hematopoietic transcriptional programs are tightly co-regulated to orchestrate a shift in cell identity. In the yolk sac, EHT generates erythro-myeloid progenitors, which upon migration to the liver differentiate into fetal blood cells, including erythrocytes and tissue-resident macrophages. In the dorsal aorta, EHT produces hematopoietic stem cells, which engraft the fetal liver and then the bone marrow to sustain adult hematopoiesis. Recent studies have defined the relationship between the developing vascular and hematopoietic systems in animal models, including molecular mechanisms that drive the hemato-endothelial transcription program for EHT. Moreover, human pluripotent stem cells have enabled modeling of fetal human hematopoiesis and have begun to generate cell types of clinical interest for regenerative medicine.

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The Winding Road of Cardiac Regeneration—Stem Cell Omics in the Spotlight

Cells ◽

10.3390/cells7120255 ◽

2018 ◽

Vol 7 (12) ◽

pp. 255 ◽

Cited By ~ 4

Author(s):

Miruna Mihaela Micheu ◽

Alina Ioana Scarlatescu ◽

Alexandru Scafa-Udriste ◽

Maria Dorobantu

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Fate ◽

Cell Biology ◽

Molecular Mechanisms ◽

Unmet Need ◽

Cardiac Regeneration ◽

Cell Types ◽

Great Promise ◽

Omics Data

Despite significant progress in treating ischemic cardiac disease and succeeding heart failure, there is still an unmet need to develop effective therapeutic strategies given the persistent high-mortality rate. Advances in stem cell biology hold great promise for regenerative medicine, particularly for cardiac regeneration. Various cell types have been used both in preclinical and clinical studies to repair the injured heart, either directly or indirectly. Transplanted cells may act in an autocrine and/or paracrine manner to improve the myocyte survival and migration of remote and/or resident stem cells to the site of injury. Still, the molecular mechanisms regulating cardiac protection and repair are poorly understood. Stem cell fate is directed by multifaceted interactions between genetic, epigenetic, transcriptional, and post-transcriptional mechanisms. Decoding stem cells’ “panomic” data would provide a comprehensive picture of the underlying mechanisms, resulting in patient-tailored therapy. This review offers a critical analysis of omics data in relation to stem cell survival and differentiation. Additionally, the emerging role of stem cell-derived exosomes as “cell-free” therapy is debated. Last but not least, we discuss the challenges to retrieve and analyze the huge amount of publicly available omics data.

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Dissecting Hes-centered transcriptional networks in neural stem cell maintenance and tumorigenesis in Drosophila

10.1101/2020.03.25.007187 ◽

2020 ◽

Cited By ~ 1

Author(s):

Srivathsa S. Magadi ◽

Chrysanthi Voutyraki ◽

Gerasimos Anagnostopoulos ◽

Evanthia Zacharioudaki ◽

Ioanna K. Poutakidou ◽

...

Keyword(s):

Stem Cells ◽

Nervous System ◽

Transcription Factor ◽

Stem Cell ◽

Neural Stem Cells ◽

Cell Fate ◽

Asymmetric Cell Division ◽

Transcriptional Networks ◽

Malignant Tumours ◽

Stem Cell Maintenance

ABSTRACTNeural stem cells divide during embryogenesis and post embryonic development to generate the entire complement of neurons and glia in the nervous system of vertebrates and invertebrates. Studies of the mechanisms controlling the fine balance between neural stem cells and more differentiated progenitors have shown that in every asymmetric cell division progenitors send a Delta-Notch signal back to their sibling stem cells. Here we show that excessive activation of Notch or overexpression of its direct targets of the Hes family causes stem-cell hyperplasias in the Drosophila larval central nervous system, which can progress to malignant tumours after allografting to adult hosts. We combined transcriptomic data from these hyperplasias with chromatin occupancy data for Dpn, a Hes transcription factor, to identify genes regulated by Hes factors in this process. We show that the Notch/Hes axis represses a cohort of transcription factor genes. These are excluded from the stem cells and promote early differentiation steps, most likely by preventing the reversion of immature progenitors to a stem-cell fate. Our results suggest that Notch signalling sets up a network of mutually repressing stemness and anti-stemness transcription factors, which include Hes proteins and Zfh1, respectively. This mutual repression ensures robust transition to neuronal and glial differentiation and its perturbation can lead to malignant transformation.

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