Yamanaka, S. & Blau, H.M. Nuclear reprogramming to a pluripotent state by three approaches. Nature 465, 704-712

Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
Nature (Impact Factor: 41.46). 06/2010; 465(7299):704-12. DOI: 10.1038/nature09229
Source: PubMed


The stable states of differentiated cells are now known to be controlled by dynamic mechanisms that can easily be perturbed. An adult cell can therefore be reprogrammed, altering its pattern of gene expression, and hence its fate, to that typical of another cell type. This has been shown by three distinct experimental approaches to nuclear reprogramming: nuclear transfer, cell fusion and transcription-factor transduction. Using these approaches, nuclei from 'terminally differentiated' somatic cells can be induced to express genes that are typical of embryonic stem cells, which can differentiate to form all of the cell types in the body. This remarkable discovery of cellular plasticity has important medical applications.


Available from: Helen M Blau, Aug 10, 2015
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    • "The discovery that transcription factors (TFs) can convert somatic cells into both specialized and induced pluripotent stem cells (iPSCs) has revolutionized stem cell research and promises to have major clinical applications (Graf and Enver, 2009; Yamanaka and Blau, 2010). Lineage-instructive TFs activate and repress tissue-specific genes by recognizing sequence-specific DNA consensus motifs contained within enhancers and promoters (Ptashne, 2007). "
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    ABSTRACT: Transcription-factor-induced somatic cell conversions are highly relevant for both basic and clinical research yet their mechanism is not fully understood and it is unclear whether they reflect normal differentiation processes. Here we show that during pre-B-cell-to-macrophage transdifferentiation, C/EBPα binds to two types of myeloid enhancers in B cells: pre-existing enhancers that are bound by PU.1, providing a platform for incoming C/EBPα; and de novo enhancers that are targeted by C/EBPα, acting as a pioneer factor for subsequent binding by PU.1. The order of factor binding dictates the upregulation kinetics of nearby genes. Pre-existing enhancers are broadly active throughout the hematopoietic lineage tree, including B cells. In contrast, de novo enhancers are silent in most cell types except in myeloid cells where they become activated by C/EBP factors. Our data suggest that C/EBPα recapitulates physiological developmental processes by short-circuiting two macrophage enhancer pathways in pre-B cells. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Stem Cell Reports 07/2015; 5(2). DOI:10.1016/j.stemcr.2015.06.007 · 5.37 Impact Factor
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    • "The TH2a/TH2b variants induce an open chromatin structure, and are enriched, and uniformly distributed both on the X chromosomes and autosomes [1]. Chromatin decondensation is a hallmark of reprogramming [10] [11]. Somatic cells can be experimentally reprogrammed back to pluripotency by nuclear transfer into oocytes [12], fusion with embryonic stem (ES) cells [13] or artificially overexpressing four transcription factors, Oct3/4, Sox2, Klf4 and c-Myc (OSKM) [14]. "
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    ABSTRACT: Histone variants TH2a and TH2b are highly expressed in testes, oocytes and zygotes. Our recent analysis suggested that these histone variants enhance the induced generation of pluripotent stem cells (iPSCs) when co-expressed along with four transcription factors, Oct3/4, Sox2, Klf4 and c-Myc (OSKM), and are associated with an open chromatin structure [1]. In the present study, we report the crystal structures of nucleosomes (NCPs) with the mouse histone variants, TH2a and TH2b. The structures revealed two significant changes, as compared to the canonical counterparts: fewer histone-DNA contacts and changes in dimer-dimer interactions between TH2a-TH2a' (L1-loop). In vivo studies with domain swapping and point mutants of the variants revealed that the residues in the histone tails and the TH2a-L1 loop are important for reprogramming. Taken together, our work indicates that the NCP variants with structural modifications and flexible tails are most likely important for enhanced reprogramming of functions. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 07/2015; 464(3). DOI:10.1016/j.bbrc.2015.07.070 · 2.30 Impact Factor
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    • "Reprogramming of somatic cells to pluripotency can be currently achieved by different methods including somatic cell nuclear transfer (SCNT), fusion of somatic and pluripotent cells, included ectopic expression of defined sets of pluripotency transcription factors (TF) in adult somatic cells to generate induced pluripotent stem cells (iPSCs), and direct reprogramming of adult somatic cells to induced neurons (iN) by empirically determined cocktails of neurogenic factors [1] [2] [3] [4] [5]. In neurodegenerative disorders where animal models have not been able to entirely recapitulate key disease pathological aspects [6], reprogramming of human fibroblasts into iPSC has become a widely used technique permitting the generation of patient-specific disease-relevant cells in virtually limitless amounts with implications for the elucidation of disease mechanisms [7]. "
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    ABSTRACT: Epigenetic mechanisms play a role in human disease but their involvement in pathologies from the central nervous system has been hampered by the complexity of the brain together with its unique cellular architecture and diversity. Until recently, disease targeted neural types were only available as postmortem materials after many years of disease evolution. Current in vitro systems of induced pluripotent stem cells (iPSCs) generated by cell reprogramming of somatic cells from patients have provided valuable disease models recapitulating key pathological molecular events. Yet whether cell reprogramming on itself implies a truly epigenetic reprogramming, the epigenetic mechanisms governing this process are only partially understood. Moreover, elucidating epigenetic regulation using patient-specific iPSC-derived neural models is expected to have a great impact to unravel the pathophysiology of neurodegenerative diseases and to hopefully expand future therapeutic possibilities. Here we will critically review current knowledge of epigenetic involvement in neurodegenerative disorders focusing on the potential of iPSCs as a promising tool for epigenetic research of these diseases.
    Stem cell International 06/2015; 2016(1). DOI:10.1155/2016/9464591 · 2.81 Impact Factor
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