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Barrero M.J.,Center for Regenerative Medicine in Barcelona | Sese B.,Center for Regenerative Medicine in Barcelona | Kuebler B.,Center for Regenerative Medicine in Barcelona | Bilic J.,Center for Regenerative Medicine in Barcelona | And 4 more authors.
Cell Reports | Year: 2013

Transcription-factor-induced reprogramming of somatic cells to pluripotency is a very inefficient process, probably due to the existence of important epigenetic barriers that are imposed during differentiation and that contribute to preserving cell identity. In an effort to decipher the molecular nature of these barriers, we followed a genome-wide approach, in which we identified macrohistone variants (macroH2A) as highly expressed in human somatic cells but downregulated after reprogramming to pluripotency, as well as strongly induced during differentiation. Knockdown of macrohistone variants in human keratinocytes increased the efficiency of reprogramming to pluripotency, whereas overexpression had opposite effects. Genome-wide occupancy profiles show that in human keratinocytes, macroH2A.1 preferentially occupies genes that are expressed at low levels and are marked with H3K27me3, including pluripotency-related genes and bivalent developmental regulators. The presence of macroH2A.1 at these genes prevents the regain of H3K4me2 during reprogramming, imposing an additional layer of repression that preserves cell identity. © 2013 The Authors. Source


Boue S.,Center for Regenerative Medicine in Barcelona | Paramonov I.,Center for Regenerative Medicine in Barcelona | Barrero M.J.,Center for Regenerative Medicine in Barcelona | Belmonte J.C.I.,Center for Regenerative Medicine in Barcelona | Belmonte J.C.I.,Salk Institute for Biological Studies
PLoS ONE | Year: 2010

After the hope and controversy brought by embryonic stem cells two decades ago for regenerative medicine, a new turn has been taken in pluripotent cells research when, in 2006, Yamanaka's group reported the reprogramming of fibroblasts to pluripotent cells with the transfection of only four transcription factors. Since then many researchers have managed to reprogram somatic cells from diverse origins into pluripotent cells, though the cellular and genetic consequences of reprogramming remain largely unknown. Furthermore, it is still unclear whether induced pluripotent stem cells (iPSCs) are truly functionally equivalent to embryonic stem cells (ESCs) and if they demonstrate the same differentiation potential as ESCs. There are a large number of reprogramming experiments published so far encompassing genome-wide transcriptional profiling of the cells of origin, the iPSCs and ESCs, which are used as standards of pluripotent cells and allow us to provide here an in-depth analysis of transcriptional profiles of human and mouse cells before and after reprogramming. When compared to ESCs, iPSCs, as expected, share a common pluripotency/self-renewal network. Perhaps more importantly, they also show differences in the expression of some genes. We concentrated our efforts on the study of bivalent domain-containing genes (in ESCs) which are not expressed in ESCs, as they are supposedly important for differentiation and should possess a poised status in pluripotent cells, i.e. be ready to but not yet be expressed. We studied each iPSC line separately to estimate the quality of the reprogramming and saw a correlation of the lowest number of such genes expressed in each respective iPSC line with the stringency of the pluripotency test achieved by the line. We propose that the study of expression of bivalent domain-containing genes, which are normally silenced in ESCs, gives a valuable indication of the quality of the iPSC line, and could be used to select the best iPSC lines out of a large number of lines generated in each reprogramming experiment. © 2010 Boué et al. Source


Li M.,Salk Institute for Biological Studies | Liu G.-H.,Salk Institute for Biological Studies | Liu G.-H.,CAS Institute of Biophysics | Belmonte J.C.I.,Salk Institute for Biological Studies | Belmonte J.C.I.,Center for Regenerative Medicine in Barcelona
Nature Reviews Molecular Cell Biology | Year: 2012

Pluripotent stem cells, which include embryonic stem cells and induced pluripotent stem cells, use a complex network of genetic and epigenetic pathways to maintain a delicate balance between self-renewal and multilineage differentiation. Recently developed high-throughput genomic tools greatly facilitate the study of epigenetic regulation in pluripotent stem cells. Increasing evidence suggests the existence of extensive crosstalk among epigenetic pathways that modify DNA, histones and nucleosomes. Novel methods of mapping higher-order chromatin structure and chromatin-nuclear matrix interactions also provide the first insight into the three-dimensional organization of the genome and a framework in which existing genomic data of epigenetic regulation can be integrated to discover new rules of gene regulation. © 2012 Macmillan Publishers Limited. All rights reserved. Source


Liu G.-H.,CAS Institute of Biophysics | Liu G.-H.,Salk Institute for Biological Studies | Ding Z.,CAS Institute of Biophysics | Izpisua Belmonte J.C.,Salk Institute for Biological Studies | Izpisua Belmonte J.C.,Center for Regenerative Medicine in Barcelona
Current Opinion in Cell Biology | Year: 2012

A global aging population, normally accompanied by a high incidence of aging-associated diseases, has prompted a renewed interest in basic research on human aging. Although encouraging progress has been achieved using animal models, the underlying fundamental mechanisms of aging remain largely unknown. Here, we review the human induced pluripotent stem cell (hiPSC)-based models of aging and aging-related diseases. These models seek to advance our knowledge of aging molecular mechanisms and help to develop strategies for treating aging-associated human diseases. © 2012 Elsevier Ltd. Source


Yi F.,Salk Institute for Biological Studies | Liu G.-H.,Salk Institute for Biological Studies | Liu G.-H.,CAS Institute of Biophysics | Belmonte J.C.I.,Salk Institute for Biological Studies | Belmonte J.C.I.,Center for Regenerative Medicine in Barcelona
Protein and Cell | Year: 2012

Recent advances in the study of human hepatocytes derived from induced pluripotent stem cells (iPSC) represent new promises for liver disease study and drug discovery. Human hepatocytes or hepatocyte-like cells differentiated from iPSC recapitulate many functional properties of primary human hepatocytes and have been demonstrated as a powerful and efficient tool to model human liver metabolic diseases and facilitate drug development process. In this review, we summarize the recent progress in this field and discuss the future perspective of the application of human iPSC derived hepatocytes. © 2012 Higher Education Press and Springer-Verlag Berlin Heidelberg. Source

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