scholarly journals Forkhead box family transcription factors as versatile regulators for cellular reprogramming to pluripotency

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Meijun Fu ◽  
Huan Chen ◽  
Zepo Cai ◽  
Yihang Yang ◽  
Ziyu Feng ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Cellular Reprogramming ◽  
Germline Transmission ◽  
Mammalian Development ◽  
Somatic Cell Reprogramming ◽  
Forkhead Box ◽  
Mesenchymal To Epithelial Transition ◽  
Induced Pluripotent ◽  
Mouse Somatic Cell

AbstractForkhead box (Fox) transcription factors play important roles in mammalian development and disease. However, their function in mouse somatic cell reprogramming remains unclear. Here, we report that FoxD subfamily and FoxG1 accelerate induced pluripotent stem cells (iPSCs) generation from mouse fibroblasts as early as day4 while FoxA and FoxO subfamily impede this process obviously. More importantly, FoxD3, FoxD4 and FoxG1 can replace Oct4 respectively and generate iPSCs with germline transmission together with Sox2 and Klf4. On the contrary, FoxO6 almost totally blocks reprogramming through inhibiting cell proliferation, suppressing the expression of pluripotent genes and hindering the process of mesenchymal to epithelial transition (MET). Thus, our study uncovers unexpected roles of Fox transcription factors in reprogramming and offers new insights into cell fate transition.

scholarly journals The Importance of Ubiquitination and Deubiquitination in Cellular Reprogramming

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Bharathi Suresh ◽  
Junwon Lee ◽  
Kye-Seong Kim ◽  
Suresh Ramakrishna
Keyword(s):  
Stem Cell ◽  
Transcription Factors ◽  
Embryonic Stem ◽  
Cellular Reprogramming ◽  
Stem Cell Maintenance ◽  
Opposite Action ◽  
Induced Pluripotent ◽  
Related Proteins ◽  
Cell Maintenance

Ubiquitination of core stem cell transcription factors can directly affect stem cell maintenance and differentiation. Ubiquitination and deubiquitination must occur in a timely and well-coordinated manner to regulate the protein turnover of several stemness related proteins, resulting in optimal embryonic stem cell maintenance and differentiation. There are two switches: an E3 ubiquitin ligase enzyme that tags ubiquitin molecules to the target proteins for proteolysis and a second enzyme, the deubiquitinating enzyme (DUBs), that performs the opposite action, thereby preventing proteolysis. In order to maintain stemness and to allow for efficient differentiation, both ubiquitination and deubiquitination molecular switches must operate properly in a balanced manner. In this review, we have summarized the importance of the ubiquitination of core stem cell transcription factors, such as Oct3/4, c-Myc, Sox2, Klf4, Nanog, and LIN28, during cellular reprogramming. Furthermore, we emphasize the role of DUBs in regulating core stem cell transcriptional factors and their function in stem cell maintenance and differentiation. We also discuss the possibility of using DUBs, along with core transcription factors, to efficiently generate induced pluripotent stem cells. Our review provides a relatively new understanding regarding the importance of ubiquitination/deubiquitination of stem cell transcription factors for efficient cellular reprogramming.

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 Dot1L methyltransferase activity is a barrier to acquisition of pluripotency but not transdifferentiation

2019 ◽  
Author(s):  
Coral K. Wille ◽  
Rupa Sridharan
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Pluripotent Stem Cells ◽  
Somatic Cells ◽  
Cell Types ◽  
Transcriptional Elongation ◽  
Mrna Levels ◽  
Mesenchymal To Epithelial Transition ◽  
Ipsc Generation ◽  
Induced Pluripotent

ABSTRACTThe ability of pluripotent stem cells to be poised to differentiate into any somatic cell type is partly derived from a unique chromatin structure that is depleted for transcriptional elongation associated epigenetic modifications, primarily H3K79 methylation. Inhibiting the H3K79 methyltransferase, Dot1L, increases the efficiency of reprogramming somatic cells to induced pluripotent stem cells (iPSCs) most potently at the mid-point of the process. Surprisingly, despite the enrichment of H3K79me2 on thousands of actively transcribed genes, Dot1L inhibition (Dot1Li) results in few changes in steady state mRNA levels during reprogramming. Dot1Li spuriously upregulates genes not involved in pluripotency and does not shutdown the somatic program. Depletion of the few genes that are downregulated, such as Nfix, enhances reprogramming efficiency in cooperation with Dot1Li. Contrary to the prevalent view, Dot1Li promotes iPSC generation beyond early phases of reprogramming such as the mesenchymal to epithelial transition and from already epithelial cell types including keratinocytes. Significantly, Dot1L inhibition does not enhance lineage conversion to neurons or muscle cells. Taken together, our results indicate that H3K79me is not a universal barrier of cell fate transitions but specifically protects somatic cells from reverting to the pluripotent state.

scholarly journals Identification of the Regulatory Elements and Target Genes of Megakaryopoietic Transcription Factor MEF2C

2019 ◽  
Vol 119 (05) ◽  
pp. 716-725 ◽  
Author(s):  
Xianguo Kong ◽  
Lin Ma ◽  
Edward Chen ◽  
Chad Shaw ◽  
Leonard Edelstein
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Genetic Variation ◽  
Transcription Factors ◽  
Cell Fate ◽  
Target Genes ◽  
Regulatory Elements ◽  
Haematopoietic Stem Cells ◽  
Platelet Production ◽  
Induced Pluripotent

AbstractMegakaryopoiesis produces specialized haematopoietic stem cells in the bone marrow that give rise to megakaryocytes which ultimately produce platelets. Defects in megakaryopoiesis can result in altered platelet counts and physiology, leading to dysfunctional haemostasis and thrombosis. Additionally, dysregulated megakaryopoiesis is also associated with myeloid pathologies. Transcription factors play critical roles in cell differentiation by regulating the temporal and spatial patterns of gene expression which ultimately decide cell fate. Several transcription factors have been described as regulating megakaryopoiesis including myocyte enhancer factor 2C (MEF2C); however, the genes regulated by MEF2C that influence megakaryopoiesis have not been reported. Using chromatin immunoprecipitation-sequencing and Gene Ontology data we identified five candidate genes that are bound by MEF2C and regulate megakaryopoiesis: MOV10, AGO3, HDAC1, RBBP5 and WASF2. To study expression of these genes, we silenced MEF2C gene expression in the Meg01 megakaryocytic cell line and in induced pluripotent stem cells by CRISPR/Cas9 editing. We also knocked down MEF2C expression in cord blood-derived haematopoietic stem cells by siRNA. We found that absent or reduced MEF2C expression resulted in defects in megakaryocytic differentiation and reduced levels of the candidate target genes. Luciferase assays confirmed that genomic sequences within the target genes are regulated by MEF2C levels. Finally, we demonstrate that small deletions linked to a platelet count-associated single nucleotide polymorphism alter transcriptional activity, suggesting a mechanism by which genetic variation in MEF2C alters platelet production. These data help elucidate the mechanism behind MEF2C regulation of megakaryopoiesis and genetic variation driving platelet production.

scholarly journals Culture Environment-Induced Pluripotency of SACK-Expanded Tissue Stem Cells

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Jean-François Paré ◽  
James L. Sherley
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Pluripotent Stem Cells ◽  
Adult Mouse ◽  
Pancreatic Tissue ◽  
Cellular Reprogramming ◽  
Induced Pluripotency ◽  
Pancreatic Stem Cells ◽  
Induced Pluripotent ◽  
Slow Growing

Previous efforts to improve the efficiency of cellular reprogramming for the generation of induced pluripotent stem cells (iPSCs) have focused mainly on transcription factors and small molecule combinations. Here, we report the results of our focus instead on the phenotype of the cells targeted for reprogramming. We find that adult mouse pancreatic tissue stem cells derived by the method of suppression of asymmetric cell kinetics (SACK) acquire increased potency simply by culture under conditions for the production and maintenance of pluripotent stem cells. Moreover, supplementation with the SACK agent xanthine, which promotes symmetric self-renewal, significantly increases the efficiency and degree of acquisition of pluripotency properties. In transplantation analyses, clonal reprogrammed pancreatic stem cells produce slow-growing tumors with tissue derivative of all three embryonic germ layers. This acquisition of pluripotency, without transduction with exogenous transcription factors, supports the concept that tissue stem cells are predisposed to cellular reprogramming, particularly when symmetrically self-renewing.

222 INCOMPLETE REPROGRAMMING OF INDUCED PLURIPOTENT STEM CELLS DERIVED FROM PORCINE FETAL FIBROBLASTS

2016 ◽  
Vol 28 (2) ◽  
pp. 242
Author(s):  
K.-H. Choi ◽  
D. Son ◽  
D.-K. Lee ◽  
J.-N. Oh ◽  
S.-H. Kim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Ectopic Expression ◽  
Cellular Reprogramming ◽  
Pluripotent State ◽  
Fetal Fibroblasts ◽  
Endogenous Genes ◽  
Induced Pluripotent

Cellular reprogramming of committed cells into a pluripotent state can be accomplished by ectopic expression of genes such as OCT4, SOX2, KLF4, and MYC. However, during reprogramming, it has been verified that failures of reactivating endogenous genes and epigenetic remodelling lead to partially reprogrammed cells exhibiting features similar to those of fully reprogrammed cells. In this study, partially reprogrammed induced pluripotent stem cells (pre-iPSC) were derived from porcine fetal fibroblasts via drug-inducible vector carrying human transcription factors (OCT4, SOX2, KLF4, and MYC). Therefore, this study aimed to investigate characteristics of pre-iPSC and reprogramming mechanisms. The pre-iPSC were stably maintained over an extended period having in vitro differentiation ability into 3 germ layers. The pluripotent state of pre-iPSC was regulated by modulation of culture condition. They showed naive- or primed-like pluripotent state in leukemia inhibitory factor (LIF) or basic fibroblast growth factor (bFGF) supplemented culture conditions respectively. However, pre-iPSC could not be maintained without ectopic expression of transgenes. The cultured pre-iPSC expressed endogenous transcription factors (OCT4 and SOX2) except for NANOG known as gateway into complete reprogramming. In addition, endogenous genes related to mesenchymal-to-epithelial transition (DPPA2, CDH1, EPCAM, and OCLN) were not sufficiently reactivated as measured by qPCR. DNA methylation analysis for promoters of OCT4, NANOG, and XIST showed that epigenetic reprogramming did not occurred in female pre-iPSC. Given the results, we found that expression of exogenous genes could not sufficiently activate the essential endogenous genes and remodel the epigenetic milieu for achieving faithful pluripotency in pig. Accordingly, investigating pre-iPSC could help us to improve and develop reprogramming methods via understanding reprogramming mechanisms in pig. This work was supported by the Next-generation BioGreen 21 Program (PJ0113002015), Rural Development Administration, Republic of Korea.

Methylation mechanisms and biomechanical effectors controlling cell fate

2018 ◽  
Vol 30 (1) ◽  
pp. 64 ◽  
Author(s):  
Tiziana A. L. Brevini ◽  
Elena F. M. Manzoni ◽  
Fulvio Gandolfi
Keyword(s):  
Cell Fate ◽  
Cell Function ◽  
Regulation Of Gene Expression ◽  
Three Dimensional ◽  
Direct Conversion ◽  
Methylation Pattern ◽  
Mammalian Development ◽  
Mesenchymal To Epithelial Transition ◽  
Tet Enzymes ◽  
Transcription Factor 4

Mammalian development and cell fate specification are controlled by multiple regulatory mechanisms that interact in a coordinated way to ensure proper regulation of gene expression and spatial restriction, allowing cells to adopt distinct differentiation traits and a terminal phenotype. For example, cell potency is modulated by changes in methylation that are under the control of methyltransferases and ten–eleven translocation (TET) enzymes, which establish or erase a phenotype-specific methylation pattern during embryo development and mesenchymal to epithelial transition (MET). Cell plasticity is also responsive to extracellular factors, such as small molecules that interact with cell fate definition and induce a transient pluripotent state that allows the direct conversion of an adult mature cell into another differentiated cell type. In addition, cell-secreted vesicles emerge as powerful effectors, capable of modifying cell function and phenotype and delivering different signals, such as octamer-binding transcription factor-4 (Oct4) and SRY (sex determining region Y)-box 2 (Sox2) mRNAs (implicated in the preservation of pluripotency), thus triggering epigenetic changes in the recipient cells. In parallel, mechanical properties of the cellular microenvironment and three-dimensional rearrangement can affect both cell potency and differentiation through marked effects on cytoskeletal remodelling and with the involvement of specific mechanosensing-related pathways.

scholarly journals Dynamic Changes in Occupancy of Histone Variant H2A.Z during Induced Somatic Cell Reprogramming

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Fulu Dong ◽  
Zhenwei Song ◽  
Jiali Yu ◽  
Baole Zhang ◽  
BaoChun Jiang ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Pluripotent Stem Cells ◽  
Chromatin Immunoprecipitation ◽  
Chromatin Modification ◽  
Cellular Reprogramming ◽  
Transcription Start ◽  
Dynamic Changes ◽  
Go Analysis ◽  
Somatic Cell Reprogramming ◽  
Induced Pluripotent

The development of induced pluripotent stem cells (iPSCs) has enabled study of the mechanisms underlying cellular reprogramming. Here, we have studied the dynamic distribution of H2A.Z during induced reprogramming with chromatin immunoprecipitation deep sequencing (ChIP-Seq). We found that H2A.Z tended to accumulate around transcription start site (TSS) and incorporate in genes with a high transcriptional activity. GO analysis with H2A.Z incorporated genes indicated that most genes are involved in chromatin assembly or disassembly and chromatin modification both in MEF and Day 7 samples, not in iPSCs. Furthermore, we detected the highest level of incorporation of H2A.Z around TSS in Day 7 samples compared to MEFs and iPSCs. GO analysis with only incorporated genes in Day 7 also displayed the function of chromatin remodeling. So, we speculate H2A.Z may be responsible for chromatin remodeling to enhance the access of transcription factors to genes important for pluripotency. This study therefore provides a deeper understanding of the mechanisms underlying induced reprogramming.

FOXO transcription factors: key regulators of cell fate

2006 ◽  
Vol 34 (5) ◽  
pp. 722-726 ◽  
Author(s):  
E.W.-F. Lam ◽  
R.E. Francis ◽  
M. Petkovic
Keyword(s):  
Oxidative Stress ◽  
Drug Resistance ◽  
Transcription Factors ◽  
Cell Fate ◽  
Environmental Cues ◽  
Cellular Functions ◽  
Forkhead Box ◽  
Foxo Transcription Factors ◽  
Stress Damage

FOXO (forkhead box O) transcription factors are crucial regulators of cell fate. This function of FOXO proteins relies on their ability to control diverse and at times, opposing cellular functions, such as proliferation, differentiation, DNA repair, defence against oxidative stress damage and apoptosis, in response to hormones, growth factors and other environmental cues. This review discusses our current understanding of the regulation and role of FOXO transcription factors in determining cell fate and highlights their relevance to tumorigenesis and drug resistance.

scholarly journals ALKBH5 regulates somatic cell reprogramming in a phase specific manner

2021 ◽  
Author(s):  
Sherif Mahrous Khodeer ◽  
Arne Klungland ◽  
John Arne Dahl
Keyword(s):  
Somatic Cell ◽  
Late Phase ◽  
Somatic Cells ◽  
Cell Reprogramming ◽  
Somatic Cell Reprogramming ◽  
Promising Tool ◽  
Mesenchymal To Epithelial Transition ◽  
Reprogramming Efficiency ◽  
Specific Manner ◽  
Induced Pluripotent

Establishment of the pluripotency regulatory network in somatic cells by introducing four transcriptional factors, (Octamer binding transcription factor 4 (OCT4), SRY (sex determining region Y)-box 2 (SOX2), Kruppel - like factor 4 (KLF4), and cellular-Myelocytomatosis (c-MYC) provides a promising tool for cell-based therapies in regenerative medicine. Still, the mechanisms at play when generating induced pluripotent stem cells from somatic cells is only partly understood. Here we show that the RNA specific N6-methyladenosine (m6A) demethylase ALKBH5 regulates somatic cell reprogramming in a stage specific manner. Knockdown or knockout of Alkbh5 in the early reprogramming phase impairs the reprogramming efficiency by reducing the proliferation rate through arresting the cells at G2/M phase and decreasing the mesenchymal-to-epithelial transition (MET) rate. However, there is no significant change in reprogramming efficiency when Alkbh5 is depleted at the late phase of reprogramming. On the other hand, ALKBH5 overexpression at the earlyreprogramming phase has no significant impact on reprogramming efficiency, while overexpression at the late phase enhances the reprogramming by stabilizing Nanog transcripts resulting in upregulated Nanog expression. Our study provides mechanistic insight into the crucial dynamic role of ALKBH5 in regulating somatic cell reprogramming at the posttranscriptional level.

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