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Transcriptional and Epigenetic Regulation of Pluripotency and Differentiation

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 33886

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Special Issue Editor

Dr. Giorgio Malpeli

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Guest Editor

Department of Human Sciences and Promotion of Quality of Life, Università Telematica San Raffaele Roma, 00166 Rome, Italy
Interests: stem cells; epigenetic mechanisms; noncoding RNAs; cancer stem cells
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In this Special Issue of Cells, we collect original discoveries and reviews on the connections between epigenetics and transcription in the regulation of pluripotency and differentiation of cells in eukaryotic species.

The plastic capacity of stem cells is an amazing paradigm in the fascinating world of cells. The commitment of stem cell to a lineage is consequential to the reprogramming of the chromatin structure and to specific changes in epigenetic signals. Understanding the different ways in which epigenetic signals and mechanisms govern transcriptional programs that support self-renewal, commitment to a lineage, and cell differentiation is a key step for advances in cell science and perspectives for medicine.

The Special Issue is open to research dealing with all kinds of aspects related to the epigenetic regulation of pluripotency and differentiation of cells in physiology and pathology, including cancer stem cells. A non-exhaustive overview of the topics of articles submitted for the Special Issue is as follows:

Epigenetic and transcriptional regulation in the maintenance of pluripotency and self-renewal.
The role of metabolism in epigenetic and transcriptional regulation in stem cell identity, reprogramming, and transdifferentiation.
Epigenetic and transcriptional regulation in lineage-restricted stem and progenitor cells.
Epigenetic states that favor the responsiveness and quiescence of stem cells.
Induced pluripotent stem cells (iPS) as a model for studying the reprogramming of cells and their epigenetic memory.
Epigenetic and transcriptional changes in cell reprogramming.
The cis and trans effects of epigenetic events that drive the self-renewal and differentiation of stem cells.
Cascades of epigenetic events associated with transcriptional programs through stem cell differentiation.
Epigenetic dynamics in the interplay between stem cells and their niche.
Cell-to-cell communication in the epigenetic and transcriptional regulation of pluripotency and differentiation.
Signaling pathways that govern epigenetic events, transcriptional programs, and the fate of stem cells.
The effects of epigenetic modifiers on transcription and the fate of cells.
The transcriptional consequences of the epigenetic control of super-enhancers in pluripotency and differentiation.
The epigenetic control of RNA stability in the maintenance of pluripotency and differentiation.
Hierarchical relationships between DNA methylation and chromatin signals in the transcriptional regulation of stem cells.
Crosstalk among noncoding RNAs, DNA methylation, and DNA-associated proteins in the transcriptional regulation of pluripotency and differentiation.
The relationship between genetic and epigenetics aspects in the transcriptional regulation of stem cells.
Somatic epigenetic variability and transcriptional control in stem cells.

We look forward to your contributions to this Special Issue.

Dr. Giorgio Malpeli
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

stem cells
cancer stem cells
pluripotency
self-renewal
cell reprogramming
cell differentiation
epigenetic signals
DNA methylation
transcriptional programs
transcription regulation

Published Papers (10 papers)

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Research

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20 pages, 5103 KiB

Open AccessArticle

Analysis of Gene Expression Patterns of Epigenetic Enzymes Dnmt3a, Tet1 and Ogt in Murine Chondrogenic Models

by Judit Vágó, Katalin Kiss, Edina Karanyicz, Roland Takács, Csaba Matta, László Ducza, Tibor A. Rauch and Róza Zákány

Cells 2021, 10(10), 2678; https://doi.org/10.3390/cells10102678 - 06 Oct 2021

Cited by 2 | Viewed by 2456

Abstract

We investigated the gene expression pattern of selected enzymes involved in DNA methylation and the effects of the DNA methylation inhibitor 5-azacytidine during in vitro and in vivo cartilage formation. Based on the data of a PCR array performed on chondrifying BMP2-overexpressing C3H10T1/2 cells, the relative expressions of Tet1 (tet methylcytosine dioxygenase 1), Dnmt3a (DNA methyltransferase 3), and Ogt (O-linked N-acetylglucosamine transferase) were further examined with RT-qPCR in murine cell line-based and primary chondrifying micromass cultures. We found very strong but gradually decreasing expression of Tet1 throughout the entire course of in vitro cartilage differentiation along with strong signals in the cartilaginous embryonic skeleton using specific RNA probes for in situ hybridization on frozen sections of 15-day-old mouse embryos. Dnmt3a and Ogt expressions did not show significant changes with RT-qPCR and gave weak in situ hybridization signals. The DNA methylation inhibitor 5-azacytidine reduced cartilage-specific gene expression and cartilage formation when applied during the early stages of chondrogenesis. In contrast, it had a stimulatory effect when added to differentiated chondrocytes, and quantitative methylation-specific PCR proved that the DNA methylation pattern of key chondrogenic marker genes was altered by the treatment. Our results indicate that the DNA demethylation inducing Tet1 plays a significant role during chondrogenesis, and inhibition of DNA methylation exerts distinct effects in different phases of in vitro cartilage formation. Full article

(This article belongs to the Special Issue Transcriptional and Epigenetic Regulation of Pluripotency and Differentiation)

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14 pages, 2467 KiB

Open AccessArticle

Differentiation of Human-Induced Pluripotent Stem Cell-Derived Endocrine Progenitors to Islet-like Cells Using a Dialysis Suspension Culture System

by Hyunjin Choi, Marie Shinohara, Masato Ibuki, Masaki Nishikawa and Yasuyuki Sakai

Cells 2021, 10(8), 2017; https://doi.org/10.3390/cells10082017 - 07 Aug 2021

Cited by 3 | Viewed by 2525

Abstract

The production of functional islet-like cells from human-induced pluripotent stem cells (hiPSCs) is a promising strategy for the therapeutic use and disease modeling for type 1 diabetes. However, the production cost of islet-like cells is extremely high due to the use of expensive growth factors for differentiation. In a conventional culture method, growth factors and beneficial autocrine factors remaining in the culture medium are removed along with toxic metabolites during the medium change, and it limits the efficient utilization of those factors. In this study, we demonstrated that the dialysis suspension culture system is possible to reduce the usage of growth factors to one-third in the differentiation of hiPSC-derived endocrine progenitor cells to islet-like cells by reducing the medium change frequency with the refinement of the culture medium. Furthermore, the expression levels of hormone-secretion-related genes and the efficiency of differentiation were improved with the dialysis suspension culture system, possibly due to the retaining of autocrine factors. In addition, we confirmed several improvements required for the further study of the dialysis culture system. These findings showed the promising possibility of the dialysis suspension culture system for the low-cost production of islet-like cells. Full article

(This article belongs to the Special Issue Transcriptional and Epigenetic Regulation of Pluripotency and Differentiation)

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16 pages, 3603 KiB

Open AccessArticle

Adipose-Derived Stem Cell Features and MCF-7

by Giuseppe Garroni, Francesca Balzano, Sara Cruciani, Renzo Pala, Donatella Coradduzza, Emanuela Azara, Emanuela Bellu, Maria Laura Cossu, Giorgio C. Ginesu, Ciriaco Carru, Carlo Ventura and Margherita Maioli

Cells 2021, 10(7), 1754; https://doi.org/10.3390/cells10071754 - 11 Jul 2021

Cited by 2 | Viewed by 3356

Abstract

Human adipose tissue-derived stem cells (hADSCs) are highly suitable for regeneration therapies being easily collected and propagated in vitro. The effects of different external factors and culturing conditions are able to affect hADSC proliferation, senescence, differentiation, and migration, even at the molecular level. In the present paper, we exposed hADSCs to an exhausted medium from the breast cancer cell line (MCF-7) to evaluate whether the soluble factors released by these cells may be able to induce changes in stem cell behavior. In particular, we investigated the expression of stemness-related genes (OCT4; Sox 2; Nanog), the cell-cycle regulators p21 (WAF1/CIP1) p53, epigenetic markers (DNMT1 and Sirt1), and autophagy-related proteins. From our results, we can infer that the exhausted medium from MCF-7 is able to influence the hADSCs behavior increasing the expression of stemness-related genes, cell proliferation, and autophagy. Polyamines detectable in MCF-7 exhausted medium could be related to the higher proliferation capability observed in hADSCs, suggesting direct crosstalk between these molecules and the observed changes in stem cell potency. Full article

(This article belongs to the Special Issue Transcriptional and Epigenetic Regulation of Pluripotency and Differentiation)

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15 pages, 2972 KiB

Open AccessArticle

The Lysine Methylase SMYD3 Modulates Mesendodermal Commitment during Development

by Raffaella Fittipaldi, Pamela Floris, Valentina Proserpio, Franco Cotelli, Monica Beltrame and Giuseppina Caretti

Cells 2021, 10(5), 1233; https://doi.org/10.3390/cells10051233 - 18 May 2021

Cited by 2 | Viewed by 2433

Abstract

SMYD3 (SET and MYND domain containing protein 3) is a methylase over-expressed in cancer cells and involved in oncogenesis. While several studies uncovered key functions for SMYD3 in cancer models, the SMYD3 role in physiological conditions has not been fully elucidated yet. Here, we dissect the role of SMYD3 at early stages of development, employing mouse embryonic stem cells (ESCs) and zebrafish as model systems. We report that SMYD3 depletion promotes the induction of the mesodermal pattern during in vitro differentiation of ESCs and is linked to an upregulation of cardiovascular lineage markers at later stages. In vivo, smyd3 knockdown in zebrafish favors the upregulation of mesendodermal markers during zebrafish gastrulation. Overall, our study reveals that SMYD3 modulates levels of mesendodermal markers, both in development and in embryonic stem cell differentiation. Full article

(This article belongs to the Special Issue Transcriptional and Epigenetic Regulation of Pluripotency and Differentiation)

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16 pages, 1745 KiB

Open AccessFeature PaperArticle

YY2 in Mouse Preimplantation Embryos and in Embryonic Stem Cells

by Raquel Pérez-Palacios, María Climent, Javier Santiago-Arcos, Sofía Macías-Redondo, Martin Klar, Pedro Muniesa and Jon Schoorlemmer

Cells 2021, 10(5), 1123; https://doi.org/10.3390/cells10051123 - 07 May 2021

Cited by 4 | Viewed by 2706

Abstract

Yin Yang 2 encodes a mammalian-specific transcription factor (YY2) that shares high homology in the zinc finger region with both YY1 and REX1/ZFP42, encoded by the Yin Yang 1 and Reduced Expression Protein 1/Zinc Finger Protein 42 gene, respectively. In contrast to the well-established roles of the latter two in gene regulation, X chromosome inactivation and binding to specific transposable elements (TEs), much less is known about YY2, and its presence during mouse preimplantation development has not been described. As it has been reported that mouse embryonic stem cells (mESC) cannot be propagated in the absence of Yy2, the mechanistic understanding of how Yy2 contributes to mESC maintenance remains only very partially characterized. We describe Yy2 expression studies using RT-PCR and staining with a high-affinity polyclonal serum in mouse embryos and mESC. Although YY2 is expressed during preimplantation development, its presence appears dispensable for developmental progress in vitro until formation of the blastocyst. Attenuation of Yy2 levels failed to alter either Zscan4 levels in two-cell embryos or IAP and MERVL levels at later preimplantation stages. In contrast to previous claims that constitutively expressed shRNA against Yy2 in mESC prohibited the propagation of mESC in culture, we obtained colonies generated from mESC with attenuated Yy2 levels. Concomitant with a decreased number of undifferentiated colonies, Yy2-depleted mESC expressed higher levels of Zscan4 but no differences in the expression of TEs or other pluripotency markers including Sox2, Oct4, Nanog and Esrrb were observed. These results confirm the contribution of Yy2 to the maintenance of mouse embryonic stem cells and show the preimplantation expression of YY2. These functions are discussed in relation to mammalian-specific functions of YY1 and REX1. Full article

(This article belongs to the Special Issue Transcriptional and Epigenetic Regulation of Pluripotency and Differentiation)

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Graphical abstract

16 pages, 1805 KiB

Open AccessFeature PaperArticle

DNMT3B Is an Oxygen-Sensitive De Novo Methylase in Human Mesenchymal Stem Cells

by Fatma Dogan, Rakad M Kh Aljumaily, Mark Kitchen and Nicholas R. Forsyth

Cells 2021, 10(5), 1032; https://doi.org/10.3390/cells10051032 - 27 Apr 2021

Cited by 6 | Viewed by 2822

Abstract

The application of physiological oxygen (physoxia) concentrations is becoming increasingly commonplace within a mammalian stem cell culture. Human mesenchymal stem cells (hMSCs) attract widespread interest for clinical application due to their unique immunomodulatory, multi-lineage potential, and regenerative capacities. Descriptions of the impact of physoxia on global DNA methylation patterns in hMSCs and the activity of enzymatic machinery responsible for its regulation remain limited. Human bone marrow-derived mesenchymal stem cells (BM-hMSCs, passage 1) isolated in reduced oxygen conditions displayed an upregulation of SOX2 in reduced oxygen conditions vs. air oxygen (21% O_2, AO), while no change was noted for either OCT-4 or NANOG. DNA methylation marks 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) showed decreases in 2% O₂ environment (workstation) (2% WKS). DNMT3B (DNA methyltransferase 3B) and TET1 (Ten-eleven translocation enzyme 1) displayed reduced transcription in physoxia. Consistent with transcriptional downregulation, we noted increased promoter methylation levels of DNMT3B in 2% WKS accompanied by reduced DNMT3B and TET1 protein expression. Finally, a decrease in HIF1A (Hypoxia-inducible factor 1A) gene expression in 2% WKS environment correlated with protein levels, while HIF2A was significantly higher in physoxia correlated with protein expression levels vs. AO. Together, these data have demonstrated, for the first time, that global 5mC, 5hmC, and DNMT3B are oxygen-sensitive in hMSCs. Further insights into the appropriate epigenetic regulation within hMSCs may enable increased safety and efficacy development within the therapeutic ambitions. Full article

(This article belongs to the Special Issue Transcriptional and Epigenetic Regulation of Pluripotency and Differentiation)

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16 pages, 5553 KiB

Open AccessArticle

Stability of Imprinting and Differentiation Capacity in Naïve Human Cells Induced by Chemical Inhibition of CDK8 and CDK19

by Raquel Bernad, Cian J. Lynch, Rocio G. Urdinguio, Camille Stephan-Otto Attolini, Mario F. Fraga and Manuel Serrano

Cells 2021, 10(4), 876; https://doi.org/10.3390/cells10040876 - 12 Apr 2021

Viewed by 3321

Abstract

Pluripotent stem cells can be stabilized in vitro at different developmental states by the use of specific chemicals and soluble factors. The naïve and primed states are the best characterized pluripotency states. Naïve pluripotent stem cells (PSCs) correspond to the early pre-implantation blastocyst and, in mice, constitute the optimal starting state for subsequent developmental applications. However, the stabilization of human naïve PSCs remains challenging because, after short-term culture, most current methods result in karyotypic abnormalities, aberrant DNA methylation patterns, loss of imprinting and severely compromised developmental potency. We have recently developed a novel method to induce and stabilize naïve human PSCs that consists in the simple addition of a chemical inhibitor for the closely related CDK8 and CDK19 kinases (CDK8/19i). Long-term cultured CDK8/19i-naïve human PSCs preserve their normal karyotype and do not show widespread DNA demethylation. Here, we investigate the long-term stability of allele-specific methylation at imprinted loci and the differentiation potency of CDK8/19i-naïve human PSCs. We report that long-term cultured CDK8/19i-naïve human PSCs retain the imprinting profile of their parental primed cells, and imprints are further retained upon differentiation in the context of teratoma formation. We have also tested the capacity of long-term cultured CDK8/19i-naïve human PSCs to differentiate into primordial germ cell (PGC)-like cells (PGCLCs) and trophoblast stem cells (TSCs), two cell types that are accessible from the naïve state. Interestingly, long-term cultured CDK8/19i-naïve human PSCs differentiated into PGCLCs with a similar efficiency to their primed counterparts. Also, long-term cultured CDK8/19i-naïve human PSCs were able to differentiate into TSCs, a transition that was not possible for primed PSCs. We conclude that inhibition of CDK8/19 stabilizes human PSCs in a functional naïve state that preserves imprinting and potency over long-term culture. Full article

(This article belongs to the Special Issue Transcriptional and Epigenetic Regulation of Pluripotency and Differentiation)

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15 pages, 4266 KiB

Open AccessArticle

Behavioral Changes in Stem-Cell Potency by HepG2-Exhausted Medium

by Francesca Balzano, Giuseppe Garroni, Sara Cruciani, Emanuela Bellu, Silvia Dei Giudici, Annalisa Oggiano, Giampiero Capobianco, Salvatore Dessole, Carlo Ventura and Margherita Maioli

Cells 2020, 9(8), 1890; https://doi.org/10.3390/cells9081890 - 12 Aug 2020

Cited by 7 | Viewed by 2914

Abstract

Wharton jelly mesenchymal stem cells (WJ-MSCs) are able to differentiate into different cell lineages upon stimulation. This ability is closely related to the perfect balance between the pluripotency-related genes, which control stem-cell proliferation, and genes able to orchestrate the appearance of a specific phenotype. Here we studied the expression of stemness-related genes, epigenetic regulators (DNMT1, SIRT1), miRNAs (miR-145, miR-148, and miR-185) related to stemness, exosomes, the cell-cycle regulators p21 (WAF1/CIP1) and p53, and the senescence-associated genes (p16, p19, and hTERT). Cells were cultured in the presence or absence of the human hepatocarcinoma cell line HepG2-exhausted medium, to evaluate changes in stemness, differentiation capability, and senescence sensibility. Our results showed the overexpression of SIRT1 and reduced levels of p21 mRNA. Moreover, we observed a downregulation of DNMT1, and a simultaneous overexpression of Oct-4 and c-Myc. These findings suggest that WJ-MSCs are more likely to retain a stem phenotype and sometimes to switch to a highly undifferentiable proliferative-like behavior if treated with medium exhausted by human HepG2 cell lines. Full article

(This article belongs to the Special Issue Transcriptional and Epigenetic Regulation of Pluripotency and Differentiation)

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Review

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32 pages, 2490 KiB

Open AccessReview

Building Pluripotency Identity in the Early Embryo and Derived Stem Cells

by Paola Rebuzzini, Maurizio Zuccotti and Silvia Garagna

Cells 2021, 10(8), 2049; https://doi.org/10.3390/cells10082049 - 10 Aug 2021

Cited by 7 | Viewed by 5574

Abstract

The fusion of two highly differentiated cells, an oocyte with a spermatozoon, gives rise to the zygote, a single totipotent cell, which has the capability to develop into a complete, fully functional organism. Then, as development proceeds, a series of programmed cell divisions occur whereby the arising cells progressively acquire their own cellular and molecular identity, and totipotency narrows until when pluripotency is achieved. The path towards pluripotency involves transcriptome modulation, remodeling of the chromatin epigenetic landscape to which external modulators contribute. Both human and mouse embryos are a source of different types of pluripotent stem cells whose characteristics can be captured and maintained in vitro. The main aim of this review is to address the cellular properties and the molecular signature of the emerging cells during mouse and human early development, highlighting similarities and differences between the two species and between the embryos and their cognate stem cells. Full article

(This article belongs to the Special Issue Transcriptional and Epigenetic Regulation of Pluripotency and Differentiation)

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18 pages, 1221 KiB

Open AccessReview

The Route of Early T Cell Development: Crosstalk between Epigenetic and Transcription Factors

by Veronica Della Chiara, Lucia Daxinger and Frank J. T. Staal

Cells 2021, 10(5), 1074; https://doi.org/10.3390/cells10051074 - 30 Apr 2021

Cited by 4 | Viewed by 4278

Abstract

Hematopoietic multipotent progenitors seed the thymus and then follow consecutive developmental stages until the formation of mature T cells. During this process, phenotypic changes of T cells entail stage-specific transcriptional programs that underlie the dynamic progression towards mature lymphocytes. Lineage-specific transcription factors are key drivers of T cell specification and act in conjunction with epigenetic regulators that have also been elucidated as crucial players in the establishment of regulatory networks necessary for proper T cell development. In this review, we summarize the activity of transcription factors and epigenetic regulators that together orchestrate the intricacies of early T cell development with a focus on regulation of T cell lineage commitment. Full article

(This article belongs to the Special Issue Transcriptional and Epigenetic Regulation of Pluripotency and Differentiation)

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