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      The roles of the reprogramming factors Oct4, Sox2 and Klf4 in resetting the somatic cell epigenome during induced pluripotent stem cell generation

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      Author(s): 1 , , 1 ,
      Publication date (Electronic):
      Journal: Genome Biology
      Publisher: BioMed Central

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          Abstract

          Somatic cell reprogramming to induced pluripotent stem (iPS) cells by defined factors is a form of engineered reverse development carried out in vitro. Recent investigation has begun to elucidate the molecular mechanisms whereby these factors function to reset the epigenome.

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          A unique chromatin signature uncovers early developmental enhancers in humans.

          Alvaro Rada-Iglesias, Ruchi Bajpai, Tomek Swigut … (2011)
          Cell-fate transitions involve the integration of genomic information encoded by regulatory elements, such as enhancers, with the cellular environment. However, identification of genomic sequences that control human embryonic development represents a formidable challenge. Here we show that in human embryonic stem cells (hESCs), unique chromatin signatures identify two distinct classes of genomic elements, both of which are marked by the presence of chromatin regulators p300 and BRG1, monomethylation of histone H3 at lysine 4 (H3K4me1), and low nucleosomal density. In addition, elements of the first class are distinguished by the acetylation of histone H3 at lysine 27 (H3K27ac), overlap with previously characterized hESC enhancers, and are located proximally to genes expressed in hESCs and the epiblast. In contrast, elements of the second class, which we term 'poised enhancers', are distinguished by the absence of H3K27ac, enrichment of histone H3 lysine 27 trimethylation (H3K27me3), and are linked to genes inactive in hESCs and instead are involved in orchestrating early steps in embryogenesis, such as gastrulation, mesoderm formation and neurulation. Consistent with the poised identity, during differentiation of hESCs to neuroepithelium, a neuroectoderm-specific subset of poised enhancers acquires a chromatin signature associated with active enhancers. When assayed in zebrafish embryos, poised enhancers are able to direct cell-type and stage-specific expression characteristic of their proximal developmental gene, even in the absence of sequence conservation in the fish genome. Our data demonstrate that early developmental enhancers are epigenetically pre-marked in hESCs and indicate an unappreciated role of H3K27me3 at distal regulatory elements. Moreover, the wealth of new regulatory sequences identified here provides an invaluable resource for studies and isolation of transient, rare cell populations representing early stages of human embryogenesis.
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            Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells.

            Ian Chambers, Douglas Colby, Morag Robertson … (2003)
            Embryonic stem (ES) cells undergo extended proliferation while remaining poised for multilineage differentiation. A unique network of transcription factors may characterize self-renewal and simultaneously suppress differentiation. We applied expression cloning in mouse ES cells to isolate a self-renewal determinant. Nanog is a divergent homeodomain protein that directs propagation of undifferentiated ES cells. Nanog mRNA is present in pluripotent mouse and human cell lines, and absent from differentiated cells. In preimplantation embryos, Nanog is restricted to founder cells from which ES cells can be derived. Endogenous Nanog acts in parallel with cytokine stimulation of Stat3 to drive ES cell self-renewal. Elevated Nanog expression from transgene constructs is sufficient for clonal expansion of ES cells, bypassing Stat3 and maintaining Oct4 levels. Cytokine dependence, multilineage differentiation, and embryo colonization capacity are fully restored upon transgene excision. These findings establish a central role for Nanog in the transcription factor hierarchy that defines ES cell identity.
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              In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state.

              Marius Wernig, Alexander Meissner, Ruth Foreman … (2007)
              Nuclear transplantation can reprogramme a somatic genome back into an embryonic epigenetic state, and the reprogrammed nucleus can create a cloned animal or produce pluripotent embryonic stem cells. One potential use of the nuclear cloning approach is the derivation of 'customized' embryonic stem (ES) cells for patient-specific cell treatment, but technical and ethical considerations impede the therapeutic application of this technology. Reprogramming of fibroblasts to a pluripotent state can be induced in vitro through ectopic expression of the four transcription factors Oct4 (also called Oct3/4 or Pou5f1), Sox2, c-Myc and Klf4. Here we show that DNA methylation, gene expression and chromatin state of such induced reprogrammed stem cells are similar to those of ES cells. Notably, the cells-derived from mouse fibroblasts-can form viable chimaeras, can contribute to the germ line and can generate live late-term embryos when injected into tetraploid blastocysts. Our results show that the biological potency and epigenetic state of in-vitro-reprogrammed induced pluripotent stem cells are indistinguishable from those of ES cells.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Genome Biol
                Journal ID (iso-abbrev): Genome Biol
                Title: Genome Biology
                Publisher: BioMed Central
                ISSN (Print): 1465-6906
                ISSN (Electronic): 1465-6914
                Publication date (Print): 2012
                Publication date (Electronic): 22 October 2012
                Publication date PMC-release: 22 October 2013
                Volume: 13
                Issue: 10
                Page: 251
                Affiliations
                [1 ]David Geffen School of Medicine, Department of Biological Chemistry, Jonsson Comprehensive Cancer Center, Molecular Biology Institute, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA 90095, USA
                Article
                Publisher ID: gb-2012-13-10-251
                DOI: 10.1186/gb-2012-13-10-251
                PMC ID: 3491406
                PubMed ID: 23088445
                SO-VID: fc9d0c1d-bc18-44a1-a094-b44bf5021158
                Copyright © Copyright ©2012 BioMed Central Ltd
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                Subject: Review

                ScienceOpen disciplines: Genetics
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                ScienceOpen disciplines: Genetics

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