scholarly journals Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Paulina A. Latos ◽  
Angela Goncalves ◽  
David Oxley ◽  
Hisham Mohammed ◽  
Ernest Turro ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Rna Polymerase Ii ◽  
Es Cells ◽  
Embryonic Stem ◽  
Transcriptional Networks ◽  
Self Renewal ◽  
Downstream Target ◽  
Trophoblast Stem

Abstract Esrrb (oestrogen-related receptor beta) is a transcription factor implicated in embryonic stem (ES) cell self-renewal, yet its knockout causes intrauterine lethality due to defects in trophoblast development. Here we show that in trophoblast stem (TS) cells, Esrrb is a downstream target of fibroblast growth factor (Fgf) signalling and is critical to drive TS cell self-renewal. In contrast to its occupancy of pluripotency-associated loci in ES cells, Esrrb sustains the stemness of TS cells by direct binding and regulation of TS cell-specific transcription factors including Elf5 and Eomes. To elucidate the mechanisms whereby Esrrb controls the expression of its targets, we characterized its TS cell-specific interactome using mass spectrometry. Unlike in ES cells, Esrrb interacts in TS cells with the histone demethylase Lsd1 and with the RNA Polymerase II-associated Integrator complex. Our findings provide new insights into both the general and context-dependent wiring of transcription factor networks in stem cells by master transcription factors.

scholarly journals KLF4 protein stability regulated by interaction with pluripotency transcription factors overrides transcriptional control

2019 ◽  
Author(s):  
Navroop K Dhaliwal ◽  
Luis E Abatti ◽  
Jennifer A Mitchell
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Protein Stability ◽  
Rna Polymerase Ii ◽  
Half Life ◽  
Transcriptional Control ◽  
Es Cells ◽  
Embryonic Stem ◽  
Post Translational Modification ◽  
Pluripotent State

AbstractEmbryonic stem (ES) cells are regulated by a network of transcription factors which maintain the pluripotent state. Differentiation relies on downregulation of pluripotency transcription factors disrupting this network. While investigating transcriptional regulation of the pluripotency transcription factor Klf4, we observed homozygous deletion of distal enhancers caused 17 fold decrease in Klf4 transcript but surprisingly decreased protein levels by less than 2 fold indicating post-transcriptional control of KLF4 protein overrides transcriptional control. The lack of sensitivity of KLF4 to transcription is due to high protein stability (half-life >24hr). This stability is context dependent and disrupted during differentiation, evidenced by a shift to a half-life of <2hr. KLF4 protein stability is maintained through interaction with other pluripotency transcription factors (NANOG, SOX2 and STAT3) that together facilitate association of KLF4 with RNA polymerase II. In addition, the KLF4 DNA binding and transactivation domains are required for optimal KLF4 protein stability. Post-translational modification of KLF4 destabilizes the protein as cells exit the pluripotent state and mutations that prevent this destabilization also prevent differentiation. These data indicate the core pluripotency transcription factors are integrated by post-translational mechanisms to maintain the pluripotent state, and identify mutations that increase KLF4 protein stability while maintaining transcription factor function.

scholarly journals RNA Polymerase II-Association Factor 1 (Paf1/PD2) Maintains Self-renewal by Its Interaction with Oct3/4 in Mouse Embryonic Stem Cells

Stem Cells ◽  
2009 ◽  
pp. N/A-N/A ◽  
Author(s):  
Moorthy P. Ponnusamy ◽  
Shonali Deb ◽  
Parama Dey ◽  
Subhankar Chakraborty ◽  
Satyanarayana Rachagani ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cells ◽  
Self Renewal

scholarly journals Unravelling evolution of Nanog, the key transcription factor involved in self-renewal of undifferentiated embryonic stem cells, by pattern recognition in nucleotide and tandem repeats characteristics

Gene ◽  
2016 ◽  
Vol 578 (2) ◽  
pp. 194-204 ◽  
Author(s):  
Maryam Pashaiasl ◽  
Khodadad Khodadadi ◽  
Amir Hossein Kayvanjoo ◽  
Roghiyeh Pashaei-asl ◽  
Esmaeil Ebrahimie ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pattern Recognition ◽  
Transcription Factor ◽  
Embryonic Stem Cells ◽  
Tandem Repeats ◽  
Embryonic Stem ◽  
Self Renewal

Tyrosine kinase signalling in embryonic stem cells

2008 ◽  
Vol 115 (2) ◽  
pp. 43-55 ◽  
Author(s):  
Cecilia Annerén
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Es Cells ◽  
Embryonic Stem ◽  
Cell Types ◽  
Self Renewal ◽  
Mouse Es Cells ◽  
Wide Range

Pluripotent ES (embryonic stem) cells can be expanded in culture and induced to differentiate into a wide range of cell types. Self-renewal of ES cells involves proliferation with concomitant suppression of differentiation. Some critical and conserved pathways regulating self-renewal in both human and mouse ES cells have been identified, but there is also evidence suggesting significant species differences. Cytoplasmic and receptor tyrosine kinases play important roles in proliferation, survival, self-renewal and differentiation in stem, progenitor and adult cells. The present review focuses on the role of tyrosine kinase signalling for maintenance of the undifferentiated state, proliferation, survival and early differentiation of ES cells.

BCR-ABL Activates STAT3 Via MEK Kinase 1 in Embryonic Stem Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4320-4320
Author(s):  
Yukinori Nakamura ◽  
Toshiaki Yujiri ◽  
Ryouhei Nawata ◽  
Kozo Tagami ◽  
Yukio Tanizawa
Keyword(s):  
Stem Cells ◽  
Alkaline Phosphatase ◽  
Phosphatase Activity ◽  
Alkaline Phosphatase Activity ◽  
Es Cells ◽  
Embryonic Stem ◽  
Myelogenous Leukemia ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Mek Kinase

Abstract BCR-ABL oncogene, the molecular hallmark of chronic myelogenous leukemia, arises in a primitive hematopoietic stem cell that has the capacity for both differentiation and self-renewal. Its product, Bcr-Abl protein, has been shown to activate STAT3 and to promote self-renewal in ES cells, even in the absence of leukemia inhibitory factor (LIF). MEK kinase 1 (MEKK1) is a 196-kDa mitogen-activated protein kinase (MAPK) kinase kinase involved in Bcr-Abl signal transduction (Oncogene22:7774, 2003). To investigate the role of MEKK1 in Bcr-Abl-induced transformation of ES cells, p210 Bcr-Abl was stably transfected into wild type (WT+p210) and MEKK1−/− (MEKK1−/−+p210) ES cells. Bcr-Abl enhanced both MEKK1 expression and activation in ES cells, as it does in other Bcr-Abl-transformed cells. In the absence of LIF, WT+p210 cells showed constitutive STAT3 activation and formed compact colonies having strong alkaline phosphatase activity, a characteristic phenotype of undifferentiated ES cells. MEKK1−/−+p210 cells, by contrast, showed less STAT3 activity than WT+p210 cells and formed large, flattened colonies having weak alkaline phosphatase activity, a phenotype of differentiated ES cells. These results indicate that MEKK1 plays an essential role in Bcr-Abl-induced STAT3 activation and in the capacity for LIF-independent self-renewal, and may thus be involved in Bcr-Abl-mediated leukemogenesis in stem cells.

scholarly journals Forced expression of Nanog in hematopoietic stem cells results in a γδT-cell disorder

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 107-115 ◽  
Author(s):  
Yosuke Tanaka ◽  
Takumi Era ◽  
Shin-ichi Nishikawa ◽  
Shin Kawamata
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Hematopoietic Stem Cells ◽  
Es Cells ◽  
Embryonic Stem ◽  
Lymphoid Tissues ◽  
Thymocyte Development ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Γδt Cell

Nanog is a key molecule involved in the maintenance of the self-renewal of undifferentiated embryonic stem (ES) cells. In this work we investigate whether Nanog can enhance self-renewal in hematopoietic stem cells. Contrary to our expectation, no positive effect of Nanog transduction was detected in bone marrow reconstitution assays. However, recipients of Nanog-transduced (Nanog) hematopoietic stem cells (HSCs) invariantly develop a unique disorder typified by an atrophic thymus occupied by Nanog-expressing γδT-cell receptor–positive (TCR+) cells (Nanog T cells). All thymi are eventually occupied by Nanog T cells with CD25+CD44+ surface phenotype that home selectively to the thymus on transfer and suppress normal thymocyte development, which is partly ascribed to destruction of the microenvironment in the thymus cortex. Moreover, this initial disorder invariantly develops to a lymphoproliferative disorder, in which Nanog T cells undergo unlimited proliferation in the peripheral lymphoid tissues and eventually kill the host. This invariable end result suggests that Nanog is a candidate oncogene for γδT-cell malignancy.

Transcription factors that behave as master regulators during mammalian embryogenesis function as molecular rheostats

2008 ◽  
Vol 411 (2) ◽  
pp. e5-e7 ◽  
Author(s):  
Angie Rizzino
Keyword(s):  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Es Cells ◽  
Embryonic Stem ◽  
Special Property ◽  
The Self ◽  
Leukaemia Inhibitory Factor ◽  
Self Renewal ◽  
Master Regulators ◽  
Mammalian Embryogenesis

Three transcription factors, Sox2, Oct-3/4 and Nanog, have been identified as master regulators that orchestrate mammalian embryogenesis as well as the self-renewal and pluripotency of ES (embryonic stem) cells. Efforts to understand how these transcription factors function have shown that they have a special property in common. Small changes in the expression of any one of these factors dramatically alter the self-renewal and pluripotency of ES cells. In this way, each functions as a molecular rheostat to control the behaviour of ES cells. Recent studies have begun to examine the molecular mechanisms that regulate the levels of these transcription factors. In this issue of the Biochemical Journal, Mullin and co-workers report that Nanog can self-associate to form dimers. Importantly, they also show that the domain responsible for dimerization is also needed for Nanog to sustain the self-renewal of ES cells in the absence of the cytokine LIF (leukaemia inhibitory factor). On the basis of their studies, they propose a novel mechanism for regulating the interactions between Nanog and other nuclear proteins.

scholarly journals Repression of Nanog Gene Transcription by Tcf3 Limits Embryonic Stem Cell Self-Renewal

2006 ◽  
Vol 26 (20) ◽  
pp. 7479-7491 ◽  
Author(s):  
Laura Pereira ◽  
Fei Yi ◽  
Bradley J. Merrill
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Regulatory Region ◽  
Embryonic Stem ◽  
Dual Function ◽  
Self Renewal ◽  
Nanog Gene

ABSTRACT The dual function of stem cells requires them not only to form new stem cells through self-renewal but also to form lineage-committed cells through differentiation. Embryonic stem cells (ESC), which are derived from the blastocyst inner cell mass, retain properties of self-renewal and the potential for lineage commitment. To balance self-renewal and differentiation, ESC must carefully control the levels of several transcription factors, including Nanog, Sox2, and Oct4. While molecular mechanisms promoting transcription of these genes have been described, mechanisms preventing excessive levels in self-renewing ESC remain unknown. By examining the function of the TCF family of transcription factors in ESC, we have found that Tcf3 is necessary to limit the steady-state levels of Nanog mRNA, protein, and promoter activity in self-renewing ESC. Chromatin immunoprecipitation and promoter reporter assays showed that Tcf3 bound to a promoter regulatory region of the Nanog gene and repressed its transcriptional activity in ESC through a Groucho interaction domain-dependent process. The absence of Tcf3 caused delayed differentiation of ESC in vitro as elevated Nanog levels persisted through 5 days of embryoid body formation. These new data support a model wherein Tcf3-mediated control of Nanog levels allows stem cells to balance the creation of lineage-committed and undifferentiated cells.

scholarly journals Resf1 supports embryonic stem cell self-renewal and effective germline entry

2021 ◽  
Author(s):  
Matus Vojtek ◽  
Ian Chambers
Keyword(s):  
Stem Cells ◽  
Germ Cell ◽  
Germ Line ◽  
Primordial Germ Cell ◽  
Embryonic Stem ◽  
Cell Specification ◽  
Self Renewal ◽  
Downstream Target ◽  
Germ Cell Specification

Retroelement silencing factor 1 (Resf1) interacts with the key regulators of mouse embryonic stem cells (ESCs) Oct4 and Nanog, and its absence results in sterility of mice. However, the function of Resf1 in ESCs and germ line specification is poorly understood. In this study, we used Resf1 knockout cell lines to determine the requirements of RESF1 for ESCs self-renewal and for in vitro specification of ESCs into primordial germ cell-like cells (PGCLCs). We found that deletion of Resf1 in ESCs cultured in serum and LIF reduces self-renewal potential whereas episomal expression of RESF1 has a modest positive effect on ESC self-renewal. In addition, RESF1 is not required for the capacity of NANOG and its downstream target ESRRB to drive self-renewal in the absence of LIF. However, Resf1 deletion reduces efficiency of PGCLC differentiation in vitro. These results identify Resf1 as a novel player in the regulation of pluripotent stem cells and germ cell specification.

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