Epigenetic modifications in the embryonic and induced pluripotent stem cells (original) (raw)
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Revista da Associacao Medica Brasileira (1992), 2017
Induced pluripotent stem cells (iPSCs) are somatic cells reprogrammed into an embryonic-like pluripotent state by the expression of specific transcription factors. iPSC technology is expected to revolutionize regenerative medicine in the near future. Despite the fact that these cells have the capacity to self-renew, they present low efficiency of reprogramming. Recent studies have demonstrated that the previous somatic epigenetic signature is a limiting factor in iPSC performance. Indeed, the process of effective reprogramming involves a complete remodeling of the existing somatic epigenetic memory, followed by the establishment of a "new epigenetic signature" that complies with the new type of cell to be differentiated. Therefore, further investigations of epigenetic modifications associated with iPSC reprogramming are required in an attempt to improve their self-renew capacity and potency, as well as their application in regenerative medicine, with a new strategy to redu...
Induced pluripotent stem cells: epigenetic memories and practical implications
Molecular Human Reproduction, 2010
Induced pluripotent stem cells (iPSCs) may be obtained by direct reprogramming of different somatic cells to a pluripotent state by forced expression of a handful of transcription factors. It was generally assumed that iPSCs are functionally equivalent to their embryonic stem cell (ESC) counterparts. Recently, a number of research groups have demonstrated that this is not the case, showing that iPSCs retain 'epigenetic memory' of the donor tissue from which they were derived and display skewed differentiation potential. This raises the question whether such cells are fit for experimental, diagnostic or therapeutic purpose. A brief survey of the literature illustrates that differences at both epigenetic and transcriptome level are observed between various pluripotent stem cell populations. Interestingly, iPSC populations with perceived 'anomalies' can be coaxed to a more ESC-like cellular state either by continuous passaging-which attenuates these epigenetic differences-or treatment with small molecules that target the machinery responsible for remodelling the genome. This suggests that the establishment of an epigenetic status approximating an ESC counterpart is largely a passive process. The mechanisms responsible remain to be established. Meanwhile, other areas of reprogramming are rapidly evolving such as, trans-differentiation of one somatic cell type to another by the forced expression of key transcription factors. When it comes to assessing their practical usefulness, the same question will also apply.
Global epigenetic changes during somatic cell reprogramming to iPS cells
Journal of molecular cell biology, 2011
Embryonic stem cells (ESCs) exhibit unique chromatin features, including a permissive transcriptional program and an open, decondensed chromatin state. Induced pluripotent stem cells (iPSCs), which are very similar to ESCs, hold great promise for therapy and basic research. However, the mechanisms by which reprogramming occurs and the chromatin organization that underlies the reprogramming process are largely unknown. Here we characterize and compare the epigenetic landscapes of partially and fully reprogrammed iPSCs to mouse embryonic fibroblasts (MEFs) and ESCs, which serves as a standard for pluripotency. Using immunofluorescence and biochemical fractionations, we analyzed the levels and distribution of a battery of histone modifications (H3ac, H4ac, H4K5ac, H3K9ac, H3K27ac, H3K4me3, H3K36me2, H3K9me3, H3K27me3, and γH2AX), as well as HP1α and lamin A. We find that fully reprogrammed iPSCs are epigenetically identical to ESCs, and that partially reprogrammed iPSCs are closer to M...
Stem cells and reprogramming: breaking the epigenetic barrier?
Trends in Pharmacological Sciences, 2011
Increasing evidence suggests that epigenetic regulation is key to the maintenance of the stem cell state. Chromatin is the physiological form of eukaryotic genomes and the substrate for epigenetic marking, including DNA methylation, post-translational modifications of histones and the exchange of core histones with histone variants. The chromatin template undergoes significant reorganization during embryonic stem cell (ESC) differentiation and somatic cell reprogramming (SCR). Intriguingly, remodeling of the epigenome appears to be a crucial barrier that must be surmounted for efficient SCR. This area of research has gained significant attention due to the importance of ESCs in modeling and treating human disease. Here we review the epigenetic mechanisms that are key for maintenance of the ESC state, ESC differentiation and SCR. We focus on murine and human ESCs and induced pluripotent stem cells, and highlight the pharmacological approaches used to study or manipulate cell fate where relevant.
Cell Stem Cell, 2011
We compared two genetically highly defined transgenic systems to identify parameters affecting reprogramming of somatic cells to a pluripotent state. Our results demonstrate that the level and stoichiometry of reprogramming factors during the reprogramming process strongly influence the resulting pluripotency of iPS cells. High expression of Oct4 and Klf4 combined with lower expression of c-Myc and Sox2 produced iPS cells that efficiently generated ''all-iPSC mice'' by tetraploid (4n) complementation, maintained normal imprinting at the Dlk1-Dio3 locus, and did not create mice with tumors. Loss of imprinting (LOI) at the Dlk1-Dio3 locus did not strictly correlate with reduced pluripotency though the efficiency of generating ''all-iPSC mice'' was diminished. Our data indicate that stoichiometry of reprogramming factors can influence epigenetic and biological properties of iPS cells. This concept complicates efforts to define a ''generic'' epigenetic state of iPSCs and ESCs and should be considered when comparing different iPS and ES cell lines.
Epigenetic regulation of human embryonic stem cells
Frontiers in Genetics, 2012
Recently, there has been tremendous progress in characterizing the transcriptional network regulating human embryonic stem cells (hESCs; MacArthur et al., 2009; Loh et al., 2011), including those signaling events mediated by Oct4, Nanog, and Sox2. There is growing interest in the epigenetic machinery involved in hESC self-renewal and differentiation. In general, epigenetic regulation includes chromatin reorganization, DNA modification, and histone modification, which are not directly related to alterations in DNA sequences. Various protein complexes, including Polycomb, trithorax, nucleosome remodeling deacetylase, SWI/SNF, and Oct4, have been shown to play critical roles in epigenetic control of hESC physiology. Hence, we will formally review recent advances in unraveling the multifaceted role of epigenetic regulation in hESC self-renewal and induced differentiation, particularly with respect to chromatin remodeling and DNA methylation events. Elucidating the molecular mechanisms underlying the maintenance/differentiation of hESCs and reprogramming of somatic cells will greatly strengthen our capacity to generate various types of cells to treat human diseases.
Stability of genomic imprinting in human induced pluripotent stem cells
BMC Genetics, 2013
Background: hiPSCs are generated through epigenetic reprogramming of somatic tissue. Genomic imprinting is an epigenetic phenomenon through which monoallelic gene expression is regulated in a parent-of-origin-specific manner. Reprogramming relies on the successful erasure of marks of differentiation while maintaining those required for genomic imprinting. Loss of imprinting (LOI), which occurs in many types of malignant tumors, would hinder the clinical application of hiPSCs.
Epigenetic memory in induced pluripotent stem cells
Nature, 2010
Somatic cell nuclear transfer and transcription-factor-based reprogramming revert adult cells to an embryonic state, and yield pluripotent stem cells that can generate all tissues. Through different mechanisms and kinetics, these two reprogramming methods reset genomic methylation, an epigenetic modification of DNA that influences gene expression, leading us to hypothesize that the resulting pluripotent stem cells might have different properties. Here we observe that low-passage induced pluripotent stem cells (iPSCs) derived by factor-based reprogramming of adult murine tissues harbour residual DNA methylation signatures characteristic of their somatic tissue of origin, which favours their differentiation along lineages related to the donor cell, while restricting alternative cell fates. Such an 'epigenetic memory' of the donor tissue could be reset by differentiation and serial reprogramming, or by treatment of iPSCs with chromatin-modifying drugs. In contrast, the differentiation and methylation of nuclear-transfer-derived pluripotent stem cells were more similar to classical embryonic stem cells than were iPSCs. Our data indicate that nuclear transfer more readily establishes the ground state of pluripotency than factor-based reprogramming, which can leave an epigenetic memory of the tissue of origin that may influence efforts at directed differentiation for applications in disease modelling or treatment.