Chromatin organization and differentiation in embryonic stem cell models

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Embryonic stem cells derived from mammalian embryos represent indispensable tools for mammalian genetics. Their key features — self-renewal and pluripotency — enable them, on the one hand, to be propagated in culture almost indefinitely and, on the other, to be used to study the molecular details of cell commitment and differentiation. In the past few years, it has become clear that chromatin and epigenetic modifications have a central role in maintaining the gene expression programs that are important for both self-renewal and cell commitment. Therefore, studies focused on the chromatin profiles of embryonic stem cells are likely to be very informative for understanding pluripotency and the process of differentiation, and ultimately for using embryonic stem cells as a tool for cell replacement therapy or as models for the study of genetic diseases, cancer progression or drug testing.

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.

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