Epigenetic Regulation of Stem Cells

10 Key excerpts on "Epigenetic Regulation of Stem Cells"

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  eBook - ePub

  The Biology and Therapeutic Application of Mesenchymal Cells

  • Kerry Atkinson(Author)
  • 2016(Publication Date)
  • Wiley-Blackwell

    (Publisher)

  Chapter 6 Epigenetic Regulation of Mesenchymal Stem/Stromal Cell Growth and Multipotentiality Sarah Elizabeth Hemming,a,b Dimitrios Cakouros,a,b and Stan Gronthos

  * a,b

  a Mesenchymal Stem Cell Laboratory, School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, South Australia, Australia

  b Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia

  Chapter Menu

  1. 6.1 Introduction
  2. 6.2 Mesenchymal Stromal/Stem Cells
  3. 6.3 Epigenetics
  4. 6.4 DNA Methylation and Histone Modifications in Mesenchymal Stem/Stromal Cells
  5. 6.5 Epigenetic Regulation of Osteogenic Differentiation
  6. 6.6 Epigenetic Regulation of Adipogenic Differentiation
  7. 6.7 Epigenetic Regulation of Myogenic Differentiation
  8. 6.8 Epigenetic Regulation of Chondrogenic Differentiation
  9. 6.9 Epigenetic Regulation of Mesenchymal Stem/Stromal Cell Lifespan and Senescence
  10. 6.10 Regulation of Epigenetic Modifications in Mesenchymal Stem/-Stromal Cells for Clinical Use
  11. 6.11 Conclusions
  12. References

  6.1 Introduction

  Mesenchymal stem/stromal cells (MSC s) are considered to be a reliable source of stem cells for cellular-based regenerative medicine applications owing to their multipotent potential, proangiogenic, and immunomodulatory properties. While the use of MSCs is less controversial than embryonic-derived stem cells (ESC s), they, like all somatic stem cells, have a finite lifespan ex vivo

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  Epigenetics and Pathology

  Exploring Connections Between Genetic Mechanisms and Disease Expression

  • Kasirajan Ayyanathan(Author)
  • 2013(Publication Date)
  • Apple Academic Press

    (Publisher)

  DNA methylation and histone modi fi cation are two important mechanisms for modulating the chromatin structure and regulating the expressions of the genes (for review, see [35]). Epigenetic regulation is a complex phenomenon that consists of a variety of different processes [21] such as imprinting [36], X chromosome inactivation [37] and gene si-lencing [38,39]. In addition it encompasses the development of an embryo [40–43] and placenta [44–46], nuclear reprogramming in SCNT embryos [3,6] and carcinogenesis [47,48]. TRANSCRIPTIONAL REGULATION The transcriptional regulation of genes is mainly directed by different strategies. These include the state of genomic methylation [21], chroma-tin configuration [49,50], chromatin structural variations (euchromatin and heterochromatin) [51,52], and chromatin modifications [53]. Chroma-tin modification in turn is influenced by methylation, acetylation and phos-phorylation, as well as polycomb proteins [54] and matrix attached region [55]. Transcriptional regulation is mostly controlled by the methylation pattern of the genome. DNA methylation on specific CpG dinucleotide (CpG) located in a cluster (CpG islands) is the regulatory mechanism by which expression of gene is either activated or suppressed (for review see [56]). Moreover, chemical modifications of chromatin histone cores are mediated by DNA methylation of CpG islands [57]. These modifications have a mutual relationship with each other [58]. Germ cells and em-bryonic cells during early development are two epigenetic sites where methylation patterns erase, establish and reestablish [59]. EPIGENETIC REPROGRAMMING DURING EMBRYOGENESIS In mammals, epigenetic reprogramming in germ cells and during pre-implantation, especially its effects on imprinting genes, predominantly establishes developmental stages [60]. The DNA methylation patterns 28 Epigenetics and Pathology characterize developmental status during cell differentiation.

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  Principles of Epigenetics

  • Vikas Mishra(Author)
  • 2019(Publication Date)
  • Delve Publishing

    (Publisher)

  In differentiated cells, signals fine-tune cell functions through changes in gene expression across the lifespan. A flexible epigenome allows us to adjust to changes in the world around us, and to “learn” from our experiences. In many ways, epigenetic expression can be thought of as the “software” of the genome and directs embryogenesis and development, as well as influences the development of an individual’s body and brain after birth. Unique sets of genes are induced or silenced epigenetically during different stages of life and these are responsible for the development and maturation of the individual through orchestrated events in combination with input from the environment. Any kind of epigenetic factors influencing genes or gene expression networks during life stages can result in an imbalance in the regulation process, and might have a life-long effect on the individual. Epigenetics Across the Human Lifespan 57 While such flexibility gives rise to beneficial adaptability to environmental conditions, it likewise allows weaknesses to integrate and exert negative and diseased outcomes on both individual and evolutionary scales. We have used data from human studies in most cases in this review, but in some cases where such data is sparse or unavailable, we have supported our explanations with data from studies on rodent and/or other animal models. From the Periconceptional Environment to Birth For most genes, total reprogramming is necessary very soon after conception in order to start with an epigenetic “clean slate,” which then allows all of the specialized cells derived from the egg and sperm to develop with stable cell-specific gene expression profiles and remain properly differentiated. This happens in the fertilized egg: global DNA demethylation is followed by remethylation to reprogram the maternal and paternal genomes for efficient gene expression regulation.

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  Insights to Neuroimmune Biology

  • Istvan Berczi(Author)
  • 2016(Publication Date)
  • Elsevier

    (Publisher)

  Stem cells are omnipotent cells, which have the capacity to regenerate, as well as rebuild all organs and tissues from injury and trauma. This cell is already handling the genome. This cell is a candidate to handle the issue of mutations and inheritance. As the stem cells are in contact with the genome of the entire organism, and possess tissue- and organ-specific stem cells (multipotent cell), it has a tremendous potential to handle mutant cells. So one has to see if epigenetic factors affect stem cells.

  2.13. Stem Cells and Epigenetic Regulation

  Findings demonstrate that pluripotent human embryonic stem cells (hESC) have a markedly different overall nuclear architecture, remodeling of which is linked to early epigenomic programming and involves formation of unique PML-defined structures.41

  DNA methylation is an important epigenetic mechanism, affecting normal development, and playing a key role in reprogramming epigenomes during stem cell derivation. Here we report on DNA methylation patterns in native monkey embryonic stem cells (ESCs), fibroblasts, and ESCs generated through somatic cell nuclear transfer (SCNT), identifying and comparing epigenome programming and reprogramming. Hundreds of regions have been characterized that are hyper- or hypomethylated in fibroblasts, compared to native ESCs, and show that these are conserved in human cells and tissues. Remarkably, a vast majority of these regions are reprogrammed in SCNT ESCs, leading to an almost perfect correlation between the epigenomic profiles of the native and reprogrammed lines. At least 58% of these changes are correlated in cis to transcription changes, Polycomb Repressive Complex-2 occupancy, or binding by the CTCF insulator. We also show that, while epigenomic reprogramming is extensive and globally accurate, the efficiency of adding and stripping DNA methylation during reprogramming is regionally variable. In several cases, this variability results in regions that remain methylated in a fibroblast-like pattern even after reprogramming.42

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  Trends in Cell Signaling Pathways in Neuronal Fate Decision

  • Sabine Wislet-Gendebien(Author)
  • 2013(Publication Date)
  • IntechOpen

    (Publisher)

  Significant differences in the miRNA expression profile was noted between these 2 human ESC lines [116], suggesting that miRNA expression patterns might dictate in defining various neuronal subtypes arisen from ESCs. 5. Conclusions Epigenetic mechanisms are regulatory processes that control gene expression via changes in chromatin structure without alterations in the DNA sequence. Changes in chromatin struc‐ ture alter the accessibility of transcription factors and RNA polymerase to genes packed into chromatin, thereby modulating the efficiency of gene transcription. Epigenetic mechanisms act to control this accessibility through histone modifications, DNA methylation, chromatin Epigenetic Regulation of Neural Differentiation from Embryonic Stem Cells http://dx.doi.org/10.5772/53650 315 remodeling, and non-coding RNAs. Each of these epigenetic events interacts with intrinsic (ex. transcription factors) and/or extrinsic factors (ex. developmental cues such as morpho‐ gens and cytokines). Studies so far have suggested that, during sequential transitions from pluripotent ESCs to terminally differentiated neurons, epigenetic mechanisms play critical roles in not only maintaining self-renewal capacity and pluripotency of ESCs, but also re‐ stricting cell lineage choices. Further investigation will therefore help clarifying the mecha‐ nisms that control pluripotency and neuronal/glial fate specification. Furthermore, the knowledge will be used in harnessing ESCs safely and effectively for clinical applications. Ackknowledgments The authors wish to thank the financial support of JSPS KAKENHI Grant Number 24592567 (to A. S.) and NIH RC1 DC010706 (to E.H.).

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  Epigenetic Gene Expression and Regulation

  • Suming Huang, Michael D. Litt, C. Ann Blakey, Michael D Litt(Authors)
  • 2015(Publication Date)
  • Academic Press

    (Publisher)

  Nat Struct Mol Biol. 2007;14(11):1025–1040.

  [48] Hosey A.M, Chaturvedi C.P, Brand M. Crosstalk between histone modifications maintains the developmental pattern of gene expression on a tissue-specific locus. Epigenetics. 2010;5(4):273–281.

  [49] Probst A.V, Dunleavy E, Almouzni G. Epigenetic inheritance during the cell cycle. Nat Rev Mol Cell Biol. 2009;10(3):192–206.

  [50] Margueron R, Reinberg D. Chromatin structure and the inheritance of epigenetic information. Nat Rev Genet. 2010;11(4):285–296.

  [51] Mansour A.A, Gafni O, Weinberger L, et al. The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming. Nature. 2012;488(7411):409–413.

  [52] Langlois T, da Costa Reis Monte Mor B, Lenglet G, et al. TET2 deficiency inhibits mesoderm and hematopoietic differentiation in human embryonic stem cells. Stem Cells. 2014.

  [53] Pasini D, Bracken A.P, Agger K, et al. Regulation of stem cell differentiation by histone methyltransferases and demethylases. Cold Spring Harb Symp Quant Biol. 2008;73:253–263.

  [54] Laugesen A, Helin K. Chromatin repressive complexes in stem cells, development, and cancer. Cell Stem Cell. 2014;14(6):735–751.

  [55] Efroni S, Duttagupta R, Cheng J, et al. Global transcription in pluripotent embryonic stem cells. Cell Stem Cell

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  Genomics

  Fundamentals and Applications

  • Supratim Choudhuri, David B. Carlson, Supratim Choudhuri, David B. Carlson(Authors)
  • 2008(Publication Date)
  • CRC Press

    (Publisher)

  2. MOLECULAR BASIS OF EPIGENETIC REGULATION Factors that chemically modify DNA without altering the sequence may alter chromatin conformation, modulate the accessibility and binding of the transcription machinery, and influence genetic regulatory cross-talk. Since all these events have downstream effects on transcription, they may trigger an epigenetic effect. Three important factors provide the molecular basis of epigenetic regulation of genome expression: (i) DNA methylation, (ii) histone modification, and (iii) noncoding RNA (ncRNA)-mediated regulation. Besides these factors, there are other mechanisms that also affect gene expression epigenetically, such as chromosome pairing-mediated changes in promoter–enhancer interaction (discussed in relation to transvection). 2.1. DNA Methylation In prokaryotes, DNA methylation occurs at both cytosine and adenine bases and is a part of the host restriction system. In multicellular eukaryotes, DNA methylation is confined to cytosine bases. Methylation involves covalent modification of cytosine at C-5 position, the methyl group donor being S -adenosylmethionine (SAM), and the enzyme involved is DNA methyltransferase (Dnmt). Cytosine methylation almost exclusively occurs on Epigenetic Regulation of Gene and Genome Expression 103 CG dinucleotide, which is denoted as CpG. The C of CpG is methylated in both strands of DNA. During replication, the parent strand is methylated, but the newly synthesized daughter strand is not methylated, thus creating a temporarily hemimethylated segment of DNA. The hemimethylated segment is recognized by maintenance methyltransferase, which methylates the hemimethylated sites and restores the parental methylation pattern. There are two types of methyltransferases: one responsible for de novo methylation that establishes the methylation pattern, and the other responsible for maintenance methylation once the methylation pattern is established.

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  Epigenomics

  From Chromatin Biology to Therapeutics

  • Krishnarao Appasani(Author)
  • 2012(Publication Date)
  • Cambridge University Press

    (Publisher)

  Indeed, the knockout of DNA methyltrans- ferases (Tsumura et al., 2006) or Polycomb repressive complex 2 (PRC2) (Chamberlain et al., 2008) does not alter self-renewing properties or the mainte- nance of cell pluripotency. These studies suggest that epigenetic mechanisms might not be essential for self-renewal and for early differentiation steps (Christophersen and Helin, 2010). However, these enzymes, as well as the marks they lay down, are essential for embryonic development (Okano et al., 1999; O’Carroll et al., 2001) and especially for embryonic stem cell full differentiation (reviewed in Meissner, 2010). While epigenetic marks may not be the key regulator of embryonic stem cell identity, they control genes involved in lineage commit- ment as well as specific parts of the genome, such as centromeres, imprinted loci, and one X chromosome in female cells. A deregulation of epigenetic modifications in embryonic stem cells might therefore not have a direct effect in undifferentiated cells but drastic consequences on their differentiated offspring, and that is of major concern for the use of pluripotent stem cells in clinics. In order to pursue the road towards therapeutic applications, these cells have to be extensively monitored in Fertilization Morula Blastocyst Differentiated tissues Human embryonic stem cells (hESCs) Human induced pluripotent stem cells (hiPSCs) Transfection with pluripotency factors Figure 9.1 Different sources of human pluripotent stem cells. These cells can be obtained by deriving human embryonic stem cells from the inner cell mass cells of blastocysts or by reprogramming adult differentiated cells into induced pluripotent stem cells. Epigenetic stability of human pluripotent stem cells 119

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  Nutrition and Epigenetics

  • Emily Ho, Frederick Domann(Authors)
  • 2014(Publication Date)
  • CRC Press

    (Publisher)

  Thus, the nucleosome, through the array of histone modi-fications it carries and the enzymes that put them in place, is a finely tuned sensor of the metabolic state of the cell and the composition of its environment. Consequently it provides a platform through which external environmental and internal variables can influence genomic function. In this manner, epigenetic states are a key modula-tor of transcriptional capacity and are regulated directly by cell context, cell cycle status, cell–cell interactions, and cell lineage commitment (reviewed by Thorne et al. 135 ). Finally, it is important to note that histone modifications, DNA methylation, and miRNA function are all intertwined. Thus, transient histone states also act as plat-forms to allow effector complexes to regulate DNA CpG methylation. For example, gene-repressive H3K9me2 associates with CpG methylation and heterochromatin. At high density regions of CpG methylation, spanning hundreds of base pairs, these marks act as triggers to recruit heterochromatin binding protein 1 (HP1). 130 The recruitment of HP1 through interaction with the methyl-CpG binding protein MBD1 leads to recruitment of both KMT1A (SUV39H1) 136 and DNA methyltransferases (DNMTs) 137 and thereby the entire region acquires H3K9 and H3K27 methylation and loses H3K4 methylation (reviewed by Cheng and Blumenthal 138 ). It has also emerged that in actively regulated regions, dynamic changes in DNA methylation appear to occur. For example, these have been measured in response to NR actions. 127–129 In parallel, increased transcriptional corepressor binding promotes direct association with the DNA methylation-dependent transcriptional repressor ZBTB33/KAISO 139 and targets DNA methylation. miRNAs control gene expression posttranscriptionally by translational inhibi-tion when base pairing between miRNA and target sequence is imperfect, while perfect or near-perfect complementarity can induce the degradation of the target mRNA.

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  Biology and Pathology of the Oocyte

  Role in Fertility, Medicine and Nuclear Reprograming

  • Alan Trounson, Roger Gosden, Ursula Eichenlaub-Ritter(Authors)
  • 2013(Publication Date)
  • Cambridge University Press

    (Publisher)

  Chapter 22: Epigenetic changes in SCNT and iPSC reprogramming spontaneously differentiate more readily into insulin- producing cells expressing PDX1 during their expan- sion in vitro. Additionally, retinal pigment epithelial cell-derived iPSCs retained their epigenetic memory despite extensive passaging and exhibited spontaneous redifferentiation [76]. The higher efficiency of iPSC differentiation to their cell type of origin may be attributable to higher transcriptional similarity between closely related cell types, and the accessibility of essential transcription cofactors may account for such higher efficiency. This could in turn reflect incomplete reprogramming, resulting in the incomplete suppression of parental cell transcription and inadequate induction of ESC fate. These reports highlight that epigenetic memory, and thus the suitability of somatic cell-derived iPSCs for translational use, is highly influenced by stochastic variations associated with laboratory-specific biases in cell culture and iPSC derivation, passage number, and mode of molecular and epigenetic analysis. These data serve as a cautionary note for the suitability of iPSCs for translational use. If iPSC products are epigeneti- cally distinct from hESCs, are functionally immature, and differ according to their cell origin, this may well deter their adoption for cell-based therapies. Conversely, the observed tendency of early-passage iPSC lines to differentiate preferentially into the cell lineage of origin could potentially be exploited in translational settings to enhance differentiation into specific and potentially elusive cell types. With these cells, it is possible to determine the epigenetic or genetic regulation of tissue development by compara- tive studies of parental, iPSC, and ESC lines. Thus, the epigenetic landscape that emerges from reprogram- ming is likely to be a sensitive indicator of its past and current developmental state and may predict its future potential.

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