Chromatin organization and differentiation in embryonic stem cell models
Introduction
The mammalian embryo provides a good source of self-renewing stem cells that can be either clonally expanded in vitro or, under certain conditions, successfully re-administered in vivo. From pre-implantation stages, pluripotent embryonic stem (ES) cells, embryonal carcinoma (EC) cells, and stem cells of trophectoderm (TS) and primitive endoderm (XEN) have been derived and characterized (Figure 1) [1, 2]. Embryonic germ (EG) cells, isolated from slightly later stages of mouse ontogeny [3], are pluripotent cells that are capable of dominant reprogramming, and that can also reset ‘parent-of-origin’ imprints [4, 5]. The lineage flexibility of embryonic stem cell lines and their tolerance for genetic modification and selection have made them indispensable tools for mammalian genetics and for exploring the molecular details of cell commitment and differentiation. In addition, their potential to offer tailored targets for cell replacement therapy has placed them high on the clinical research agenda. Here, we review some of the recent studies in which embryo-derived stem cells have been used to demonstrate the unusual chromatin configuration of pluripotent cells and the epigenetic changes that accompany lineage induction.
Section snippets
ES cells and lineage induction
ES cells were first isolated in 1981 from the inner cell mass (ICM) of developing mouse blastocysts [6, 7]. Although these cells are normally pluripotent for only a short time within the developing embryo, under appropriate conditions they can be propagated and expanded in vitro, while remaining in an undifferentiated state [8]. Just as their normal counterparts go on to contribute to foetal ectoderm, mesoderm and endoderm tissues, ES cells can generate an array of different cell types,
Chromatin bivalency in ES cells
In a developing multi-cellular organism, specific transcriptional programs are active only in a subset of cells, and the progeny of these specialized cells are able to transmit their gene expression profile through subsequent cell divisions. Although we do not yet fully understand how patterns of gene expression are transmitted from mother to daughter cell, the requirement for Trithorax and Polycomb proteins for maintaining the correct epigenetic inheritance of expressed and inactive genes
Chromatin changes in response to differentiation
Various chromatin remodeling events are known to occur in response to differentiation, including covalent modification of histone tails at specific loci, incorporation of variant histones, changes in DNA methylation, nucleosome repositioning and both global and local changes in chromatin and DNA accessibility. Several reports have also suggested changes in the dynamics and organization of chromatin in differentiating ES cells. These include the reorganization of heterochromatin and associated
Nuclear reorganization in differentiating ES cells
There is now a wealth of information from studies in human, mouse and flies to show that genes occupy non-random positions in the cell nucleus and that their proximity to specific landmarks, such as heterochromatin or the nuclear periphery [37, 38, 43], as well as to other genes [41, 55], changes according to the cell type, its stage of cell cycle and the transcription state of the gene or its immediate neighbors [47, 56]. Higher-order chromatin structure involving large regions of the genome
Conclusions and prospects
In summary, recent advances in understanding how to induce ES cells to differentiate in a homogenous fashion along a specific lineage pathway have offered molecular biologists an unrivalled opportunity to examine how lineage choice and cell specification operates during embryogenesis. This advance, when coupled with modern genome-wide approaches that survey gene expression and chromatin profiles of differentiating cells, promises to provide us with an enlightened view of how lineage restriction
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank Helle Jørgensen for communicating unpublished results, and the Medical Research Council (MRC) UK for continuing support to SG, MD and AGF.
References (83)
- et al.
Guiding embryonic stem cells towards differentiation: lessons from molecular embryology
Curr Opin Genet Dev
(2006) - et al.
Signalling, cell cycle and pluripotency in embryonic stem cells
Trends Cell Biol
(2002) - et al.
Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity
Neuron
(2000) - et al.
Direct neural fate specification from embryonic stem cells: a primitive mammalian neural stem cell stage acquired through a default mechanism
Neuron
(2001) - et al.
Embryonic stem cells express neuronal properties in vitro
Dev Biol
(1995) - et al.
Regionalization and fate specification in neurospheres: the role of Olig2 and Pax6
Mol Cell Neurosci
(2004) - et al.
Neuronal differentiation following transplantation of expanded mouse neurosphere cultures derived from different embryonic forebrain regions
Exp Neurol
(2003) - et al.
Development of the hemangioblast defines the onset of hematopoiesis in human ES cell differentiation cultures
Blood
(2006) - et al.
Molecular control of pluripotency
Curr Opin Genet Dev
(2006) - et al.
Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins
Annu Rev Genet
(2004)