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. 2011 Apr;2(1):27-53.
doi: 10.1007/s13148-010-0016-0. Epub 2010 Dec 17.

Molecular marks for epigenetic identification of developmental and cancer stem cells

Molecular marks for epigenetic identification of developmental and cancer stem cells

Samir Kumar Patra et al. Clin Epigenetics. 2011 Apr.

Abstract

Epigenetic regulations of genes by reversible methylation of DNA (at the carbon-5 of cytosine) and numerous reversible modifications of histones play important roles in normal physiology and development, and epigenetic deregulations are associated with developmental disorders and various disease states, including cancer. Stem cells have the capacity to self-renew indefinitely. Similar to stem cells, some malignant cells have the capacity to divide indefinitely and are referred to as cancer stem cells. In recent times, direct correlation between epigenetic modifications and reprogramming of stem cell and cancer stem cell is emerging. Major discoveries were made with investigations on reprogramming gene products, also known as master regulators of totipotency and inducer of pluoripotency, namely, OCT4, NANOG, cMYC, SOX2, Klf4, and LIN28. The challenge to induce pluripotency is the insertion of four reprogramming genes (Oct4, Sox2, Klf4, and c-Myc) into the genome. There are always risks of silencing of these genes by epigenetic modifications in the host cells, particularly, when introduced through retroviral techniques. In this contribution, we will discuss some of the major discoveries on epigenetic modifications within the chromatin of various genes associated with cancer progression and cancer stem cells in comparison to normal development of stem cell. These modifications may be considered as molecular signatures for predicting disorders of development and for identifying disease states.

Electronic supplementary material: The online version of this article (doi:10.1007/s13148-010-0016-0) contains supplementary material, which is available to authorized users.

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Figures

Scheme 1
Scheme 1
Levels of stem-cell state
Fig. 1
Fig. 1
Embryo development and epigenetic reprogramming cycle. Epigenetic modifications take place in two phases during the embryo development. Fertilization signals the reprogramming during preimplantation development. I-A In preimplantation development just after fertilization, DNA demethylation takes place in male pronucleus but female pronucleus remains unchanged. I-B Thereafter, both genomes are passively demethylated, except at imprinted genes and some transposons, for several rounds of cell division. This demethylation occurs due to disruption of maintenance methylation mechanism. I-C The genome is de novo methylated around the blastocyst stage, which responsible for differentiation of the first two lineages of the blastocyst stage, the inner cell mass (ICM) and the trophectoderm. All embryonic lineages differentiate from the ICM. II-A PGCs arise from somatic tissue and develop into mature gametes during gametogenesis stage. Their genome undergoes DNA demethylation in the embryo between day 11.5 and 12.5, including all imprinted genes. II-B Following demethylation, the genomes of the gametes are de novo methylated and acquire imprints; this process continues up to 18.5 in males and in maturing oocytes before ovulation in females
Fig. 2
Fig. 2
During early embryogenesis, master transcriptional regulatory genes and signaling pathways play essential roles in cell line differentiation. Esrrb, Tbx3 and Tcl1, as well as Nanog, Oct4 and Sox2, are required for self-renewal property of ES cells. Oct4 is required to prevent trophectodermal differentiation; Nanog and Sox2 appear to be global regulators that repress multiple differentiation programs, whereas Esrrb, Tbx3 and Tcl1 are essential to block the differentiation into epiblast-derived lineages. These regulators couple with transcriptional network and control the expression ofdifferent genes through distinct molecular pathways. Downregulation of Nanog, SOX2, ESRRB, Tbx3 or TCL1 leads to the immediate induction of Otx2 (orthodenticle homolog 2), Pitx2 (paired-like homeodomain transcription factor-2), Sox18 (SRY (Sex determining region Y)-box 18), and probably additional genes, which help in the differentiation of cell lineages in epiblast. Tead4 expresses when Oct4, Nanog and Sox2 are repressed. Tead4 expression is responsible for Cdx2 gene expression that is nesessary for placenta development. Nanog directly repress GATA6, which results in repression of GATA4, thereby inhibiting primitive endoderm differentiation

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