Oct4 dependence of chromatin structure within the extended Nanog locus in ES cells.

Division of Hematology-Oncology, Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02115, USA.
Genes & Development (Impact Factor: 12.64). 04/2008; 22(5):575-80. DOI: 10.1101/gad.1606308
Source: PubMed

ABSTRACT Embryonic stem (ES) cells offer insight into early developmental fate decisions, and their controlled differentiation may yield vast regenerative potential. The molecular determinants supporting ES cell self-renewal are incompletely understood. The homeodomain proteins Nanog and Oct4 are essential for mouse ES cell self-renewal. Using a high-throughput approach, we discovered DNaseI hypersensitive sites and potential regulatory elements along a 160-kb region of the genome that includes GDF3, Dppa3, and Nanog. We analyzed gene expression, chromatin occupancy, and higher-order chromatin structure throughout this gene locus and found that expression of the reprogramming factor Oct4 is required to maintain its integrity.

  • [Show abstract] [Hide abstract]
    ABSTRACT: High-throughput methods based on chromosome conformation capture have greatly advanced our understanding of the three-dimensional (3D) organization of genomes but are limited in resolution by their reliance on restriction enzymes. Here we describe a method called DNase Hi-C for comprehensively mapping global chromatin contacts. DNase Hi-C uses DNase I for chromatin fragmentation, leading to greatly improved efficiency and resolution over that of Hi-C. Coupling this method with DNA-capture technology provides a high-throughput approach for targeted mapping of fine-scale chromatin architecture. We applied targeted DNase Hi-C to characterize the 3D organization of 998 large intergenic noncoding RNA (lincRNA) promoters in two human cell lines. Our results revealed that expression of lincRNAs is tightly controlled by complex mechanisms involving both super-enhancers and the Polycomb repressive complex. Our results provide the first glimpse of the cell type-specific 3D organization of lincRNA genes.
    Nature Methods 12/2014; DOI:10.1038/nmeth.3205 · 25.95 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Since the first prospective identification of cancer stem cells in solid cancers the cancer stem cell hypothesis has reemerged as a research topic of increasing interest. It postulates that solid cancers are organized hierarchically with a small number of cancer stem cells driving tumor growth, repopulation after injury and metastasis. They give rise to differentiated progeny, which lack these features. The model predicts that for any therapy to provide cure, all cancer stem cells have to be eliminated while the survival of differentiated progeny is less critical. In this review we discuss recent reports challenging the idea of a unidirectional differentiation of cancer cells. These reports provide evidence supporting the idea that non-stem cancer cells exhibit a remarkable degree of plasticity that allows them to re-acquire cancer stem cell traits, especially in the context of radiation therapy. We summarize conditions under which differentiation is reversed and discuss the current knowledge of the underlying mechanisms.
    Seminars in Cancer Biology 07/2014; DOI:10.1016/j.semcancer.2014.07.001 · 9.14 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pairing of homologous alleles is a phenomenon generally associated with imprinted and mono-allelically expressed loci. In this issue, Hogan et al. (2015) examine the earliest steps between pluripotency and lineage commitment in ESCs and find a critical role for transient pairing of Oct4 alleles in exiting the pluripotent state. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell Stem Cell 03/2015; 16(3):213-124. DOI:10.1016/j.stem.2015.02.009 · 22.15 Impact Factor

Full-text (2 Sources)

Available from
May 26, 2014