Switching genes on and off in haemopoiesis

2008 ◽  
Vol 36 (4) ◽  
pp. 613-618 ◽  
Author(s):  
David Garrick ◽  
Marco De Gobbi ◽  
Magnus Lynch ◽  
Douglas R. Higgs
Keyword(s):  
Stem Cells ◽  
Histone Deacetylases ◽  
Gene Locus ◽  
Molecular Mechanisms ◽  
Terminal Differentiation ◽  
Lineage Commitment ◽  
Clinical Settings ◽  
Globin Genes ◽  
Specific Manner ◽  
Polycomb Complex

At present, the molecular mechanisms by which stem cells commit to and differentiate towards specific lineages are poorly characterized, and will need to be better understood before stem cells can be exploited fully in experimental and clinical settings. Transcriptional regulation, the ability to turn genes on and off, lies at the heart of these processes of lineage commitment and specification. We have focused on fully understanding how these decisions are made at a single mammalian gene locus, the α-globin genes, which become up-regulated in a tissue- and developmental-stage specific manner during haemopoiesis. The studies summarized in the present article have revealed that complete regulation of this gene cluster involves not only activating mechanisms in expressing erythroid cells, but also repressing mechanisms, involving the Polycomb complex and histone deacetylases which are present in non-erythroid tissues. Taken together, these observations provide a well-characterized model of how gene expression is fully regulated during the transition from stem cells through lineage commitment and terminal differentiation.

scholarly journals Histone Deacetylases in Neural Stem Cells and Induced Pluripotent Stem Cells

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Guoqiang Sun ◽  
Chelsea Fu ◽  
Caroline Shen ◽  
Yanhong Shi
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Self Renewal ◽  
Stem Cell Pluripotency ◽  
Induced Pluripotent

Stem cells have provided great hope for the treatment of a variety of human diseases. However, the molecular mechanisms underlying stem cell pluripotency, self-renewal, and differentiation remain to be unveiled. Epigenetic regulators, including histone deacetylases (HDACs), have been shown to coordinate with cell-intrinsic transcription factors and various signaling pathways to regulate stem cell pluripotency, self-renewal, and fate determination. This paper focuses on the role of HDACs in the proliferation and neuronal differentiation of neural stem cells and the application of HDAC inhibitors in reprogramming somatic cells to induced pluripotent stem cells (iPSCs). It promises to be an active area of future research.

The Balance of Gfi-1 and Gfi-1b Maintains the Undifferentiated, Multipotent State of Hematopoietic Stem Cells and Regulates Lineage-Commitment

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1210-1210
Author(s):  
Adlen Foudi ◽  
Hanno Hock
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Global Gene Expression ◽  
Family Factors ◽  
Lineage Commitment ◽  
Hematopoietic Stem ◽  
Global Gene Expression Profiling

Abstract Abstract 1210 Gfi-1 and Gfi-1b are homologous transcriptional repressors that are expressed in hematopoietic stem cells (HSCs). Gfi-1 is crucial for the terminal maturation of neutrophils, and Gfi-1b is critical for erythropoiesis and thrombopoiesis. HSCs give rise to all mature blood lineages through a tightly regulated multistep differentiation process, but the mechanism of their early lineage specification remains largely elusive. Here, we have dissected the role of the Gfi-family factors in HSC maintenance and early lineage-commitment. To this end, we generated conditional targeted alleles for Gfi-1 and Gfi-1b that allowed for time controlled induced disruption of their genes. Acute disruption of Gfi-1 resulted in a rapid, severe decrease of HSCs numbers in the bone marrow and ablated their function in competitive repopulation assays. Surprisingly, and sharply contradicting recent claims to the opposite, acute disruption of Gfi-1b also led to decreased numbers of long-term repopulating HSCs in the bone marrow and decreased fitness in competitive transplantation. After induced, combined disruption of both factors, no HSC and progenitor cells were maintained in the bone marrow for more than 2 weeks. To elucidate the molecular mechanisms of the Gfi-family mediated HSC maintenance we performed global gene expression profiling of Gfi-1−/− and Gfi-1b−/− HSCs. Unexpectedly, both factors regulate highly distinct gene sets involved in differentiation of alternative lineages. Thus, surprisingly, their action in HSCs is not redundant but synergistic. Consistent with this, disruption of individual Gfi-family factors renders HSCs prone to differentiation to specific alternative lineages, while combined disruption is entirely incompatible with HSCs maintenance, in large part due to unchecked differentiation. Together, our data reveal that balanced expression of Gfi-1 and Gfi-1b is required for maintaining the undifferentiated, multipotent state of HSCs, while altering the balance is sufficient for inducing commitment to specific lineages. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The role of the polycomb complex in silencing α-globin gene expression in nonerythroid cells

Blood ◽  
2008 ◽  
Vol 112 (9) ◽  
pp. 3889-3899 ◽  
Author(s):  
David Garrick ◽  
Marco De Gobbi ◽  
Vasiliki Samara ◽  
Michelle Rugless ◽  
Michelle Holland ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Globin Gene ◽  
Cpg Islands ◽  
Gene Activation ◽  
Globin Genes ◽  
Erythroid Cells ◽  
Polycomb Complex ◽  
Globin Gene Expression

Although much is known about globin gene activation in erythroid cells, relatively little is known about how these genes are silenced in nonerythroid tissues. Here we show that the human α- and β-globin genes are silenced by fundamentally different mechanisms. The α-genes, which are surrounded by widely expressed genes in a gene dense region of the genome, are silenced very early in development via recruitment of the Polycomb (PcG) complex. By contrast, the β-globin genes, which lie in a relatively gene-poor chromosomal region, are not bound by this complex in nonerythroid cells. The PcG complex seems to be recruited to the α-cluster by sequences within the CpG islands associated with their promoters; the β-globin promoters do not lie within such islands. Chromatin associated with the α-globin cluster is modified by histone methylation (H3K27me3), and silencing in vivo is mediated by the localized activity of histone deacetylases (HDACs). The repressive (PcG/HDAC) machinery is removed as hematopoietic progenitors differentiate to form erythroid cells. The α- and β-globin genes thus illustrate important, contrasting mechanisms by which cell-specific hematopoietic genes (and tissue-specific genes in general) may be silenced.

scholarly journals Pathological LSD1 mutations cause HDAC-mediated aberrant gene repression during early cell differentiation

2021 ◽  
Author(s):  
Daria Bunina ◽  
Pierre-Luc Germain ◽  
Alejandro Lopez Tobon ◽  
Nadine Fernandez-Novel Marx ◽  
Christian Arnold ◽  
...  
Keyword(s):  
Stem Cells ◽  
Protein Function ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Differentiated Cells ◽  
Lineage Differentiation ◽  
Lysine Specific Demethylase

Lysine-specific demethylase 1 (LSD1/KDM1A) removes methylation of histone and non-histone substrates, and recruits a repressive chromatin complex. De novo LSD1 mutations impairing protein function lead to a rare neurodevelopmental disorder, but the molecular mechanisms of the pathology are unclear. Using patient-derived fibroblasts, reprogrammed pluripotent stem cells, and differentiated cells, we found over 4000 differentially expressed genes and 68 transcription factors (TFs) whose motif accessibilities changed upon LSD1 mutation. An enhancer-mediated gene regulatory network approach identified impaired transcriptional repressor activity in fibroblast and stem cells, leading to erroneous activation of their target genes. Furthermore, our analysis revealed overall decreases in TF target genes specifically during early lineage differentiation of LSD1 mutant stem cells, likely caused by increased activity of repressive co-factors of LSD1 - histone deacetylases (HDACs). Consistently, HDAC inhibitor restored changes in gene expression including downregulation phenotype. Our findings provide insights into pathogenesis of LSD1 mutations and targets for further therapeutic studies.

scholarly journals Nodal-dependent Cripto signaling promotes cardiomyogenesis and redirects the neural fate of embryonic stem cells

2003 ◽  
Vol 163 (2) ◽  
pp. 303-314 ◽  
Author(s):  
Silvia Parisi ◽  
Daniela D'Andrea ◽  
Carmine T. Lago ◽  
Eileen D. Adamson ◽  
M. Graziella Persico ◽  
...  
Keyword(s):  
Stem Cells ◽  
Molecular Mechanisms ◽  
Es Cells ◽  
Embryonic Stem ◽  
Terminal Differentiation ◽  
Direct Conversion ◽  
Type I ◽  
Neural Fate ◽  
Timing Of Initiation

The molecular mechanisms controlling inductive events leading to the specification and terminal differentiation of cardiomyocytes are still largely unknown. We have investigated the role of Cripto, an EGF-CFC factor, in the earliest stages of cardiomyogenesis. We find that both the timing of initiation and the duration of Cripto signaling are crucial for priming differentiation of embryonic stem (ES) cells into cardiomyocytes, indicating that Cripto acts early to determine the cardiac fate. Furthermore, we show that failure to activate Cripto signaling in this early window of time results in a direct conversion of ES cells into a neural fate. Moreover, the induction of Cripto activates the Smad2 pathway, and overexpression of activated forms of type I receptor ActRIB compensates for the lack of Cripto signaling in promoting cardiomyogenesis. Finally, we show that Nodal antagonists inhibit Cripto-regulated cardiomyocyte induction and differentiation in ES cells. All together our findings provide evidence for a novel role of the Nodal/Cripto/Alk4 pathway in this process.

A common mechanism links activities of butyrate in the colon

2017 ◽  
Author(s):  
Mohit S. Verma ◽  
Michael J. Fink ◽  
Gabriel L Salmon ◽  
Nadine Fornelos ◽  
Takahiro E. Ohara ◽  
...  
Keyword(s):  
Stem Cells ◽  
Histone Deacetylases ◽  
Biological Activities ◽  
Short Chain Fatty Acids ◽  
Common Mechanism ◽  
Epithelial Stem Cells ◽  
Degree Of Unsaturation ◽  
Structure Activity ◽  
Starting Point ◽  
New Compounds

Two biological activities of butyrate in the colon (suppression of proliferation of colonic epithelial stem cells and inflammation) correlate with inhibition of histone deacetylases. Cellular and biochemical studies of molecules similar in structure to butyrate, but different in molecular details (functional groups, chain-length, deuteration, oxidation level, fluorination, or degree of unsaturation) demonstrated that these activities were sensitive to molecular structure, and were compatible with the hypothesis that butyrate acts by binding to the Zn<sup>2+</sup> in the catalytic site of histone deacetylases. Structure-activity relationships drawn from a set of 36 compounds offer a starting point for the design of new compounds targeting the inhibition of histone deacetylases. The observation that butyrate was more potent than other short-chain fatty acids is compatible with the hypothesis that crypts evolved (at least in part), to separate stem cells at the base of crypts from butyrate produced by commensal bacteria.

Molecular Mechanisms Underlying the Functions of Cellular Markers Associated with the Phenotype of Cancer Stem Cells

2019 ◽  
Vol 14 (5) ◽  
pp. 405-420 ◽  
Author(s):  
Eduardo Alvarado-Ortiz ◽  
Miguel Á. Sarabia-Sánchez ◽  
Alejandro García-Carrancá
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Molecular Mechanisms ◽  
Tumor Biology ◽  
Molecular Tools ◽  
Recent Past ◽  
Functional Roles ◽  
Cellular Population ◽  
Cellular Markers ◽  
A Minor

Cancer Stem Cells (CSC) generally constitute a minor cellular population within tumors that exhibits some capacities of normal Stem Cells (SC). The existence of CSC, able to self-renew and differentiate, influences central aspects of tumor biology, in part because they can continue tumor growth, give rise to metastasis, and acquire drug and radioresistance, which open new avenues for therapeutics. It is well known that SC constantly interacts with their niche, which includes mesenchymal cells, extracellular ligands, and the Extra Cellular Matrix (ECM). These interactions regularly lead to homeostasis and maintenance of SC characteristics. However, the exact participation of each of these components for CSC maintenance is not clear, as they appear to be context- or cell-specific. In the recent past, surface cellular markers have been fundamental molecular tools for identifying CSC and distinguishing them from other tumor cells. Importantly, some of these cellular markers have been shown to possess functional roles that affect central aspects of CSC. Likewise, some of these markers can participate in regulating the interaction of CSC with their niche, particularly the ECM. We focused this review on the molecular mechanisms of surface cellular markers commonly employed to identify CSC, highlighting the signaling pathways and mechanisms involved in CSC-ECM interactions, through each of the cellular markers commonly used in the study of CSC, such as CD44, CD133, CD49f, CD24, CXCR4, and LGR5. Their presence does not necessarily implicate them in CSC biology.

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