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  • Review Article
  • Published:

Chromatin remodelling in mammalian differentiation: lessons from ATP-dependent remodellers

Nature Reviews Genetics volume 7, pages 461–473 (2006)Cite this article

Key Points

  • ATP-dependent chromatin-remodelling enzymes use the energy of ATP hydrolysis to alter histone–DNA contacts and to facilitate changes in chromatin structure. These are important steps in the regulation of gene expression, recombination and cell-cycle progression during cell differentiation.

  • ATP-dependent chromatin-remodelling enzymes contribute to, and in many cases are essential for, organismal development and the initiation and/or completion of mammalian differentiation processes.

  • The complexity of ATP-dependent chromatin-remodelling enzyme function might be increased by the presence of tissue-specific subunits and the ability to form different complexes from a pool of different subunit proteins.

  • ATP-dependent chromatin-remodelling can be regulated by signal transduction pathways, thereby permitting extracellular cues to exert effects on chromatin structure.

  • Regulation of changes in chromatin structure at specific loci frequently occurs in cooperation with chromatin modifying enzymes that post-translationally modify histone proteins.

  • ATP-dependent chromatin-remodelling enzymes can have local effects on chromatin structure at specific loci, and can also have long-range effects that mediate changes over several kilobases or more.

  • The targeting of ATP-dependent chromatin-remodelling enzymes to their sites of action occurs via DNA-binding regulatory factors that promote specific differentiation pathways. Targeting by related factors during differentiation might help to explain differences in the extent and timing of changes in chromatin structure and subsequent changes in gene expression.

  • During the regulation of differentiation-specific gene expression, the consequences of ATP-dependent remodelling can result in gene activation or gene silencing. Moreover, the requirement for specific enzymes seems to be locus specific, despite the fact that multiple genes are responding to the differentiation cues with similar kinetics.

Abstract

The initiation of cellular differentiation involves alterations in gene expression that depend on chromatin changes, at the level of both higher-order structures and individual genes. Consistent with this, chromatin-remodelling enzymes have key roles in differentiation and development. The functions of ATP-dependent chromatin-remodelling enzymes have been studied in several mammalian differentiation pathways, revealing cell-type-specific and gene-specific roles for these proteins that add another layer of precision to the regulation of differentiation. Recent studies have also revealed a role for ATP-dependent remodelling in regulating the balance between proliferation and differentiation, and have uncovered intriguing links between chromatin remodelling and other cellular processes during differentiation, including recombination, genome organization and the cell cycle.

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Figure 1: ATP-dependent chromatin-remodelling enzymes.
Figure 2: Long-range control of expression at the interleukin-2α locus is mediated by ATP-dependent chromatin remodelling.
Figure 3: Temporal requirement for chromatin remodelling at the myogenin locus.

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Acknowledgements

This work was supported by grants from the American Heart Association and the National Institutes of Health (NIH) to I.L.D. and from the NIH to A.N.I. We apologize to those whose work was not discussed due to space limitations.

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  1. Department of Biochemistry and Cancer Biology, Medical University of Ohio, 3035 Arlington Avenue, Toledo, 43606, Ohio, USA

    Ivana L. de la Serna

  2. Department of Cell Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, 01655, Massachusetts, USA

    Yasuyuki Ohkawa & Anthony N. Imbalzano

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Glossary

Myeloid cells

General term for white blood cells that are not of the lymphoid lineage that gives rise to cells such as T and B cells. Myeloid cells arise in the bone marrow and include megakaryocytes, monocytes and granulocytes.

Homeobox genes

A family of genes that are critically important for many aspects of development. They often encode transcription factors that regulate the expression of many other genes. The proteins encoded contain homeoboxes, a specific class of DNA-binding domain.

Polycomb group proteins

A class of proteins — originally described in Drosophila melanogaster — that maintain the stable and heritable repression of several genes, including the homeotic genes.

T cell

T cells are derived from precursor cells that arise in the bone marrow and then collect in the thymus as thymocytes, where they undergo differentiation. T cells recognize antigens through cell-surface receptors, and exert different effects depending on whether they differentiate to form cytotoxic or helper T cells.

Helper T cells

When stimulated by a specific antigen, these cells release specific lymphokines that promote the activation and function of cytotoxic T cells and of antibody-producing B cells.

Cytotoxic T cells

Also called killer T cells; these cells recognize and lyse target cells bearing a specific foreign antigen.

Pre-initiation complex

A complex consisting of a specific RNA polymerase and its associated factors that interact with promoter DNA near the RNA start site and are necessary to initiate transcription.

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de la Serna, I., Ohkawa, Y. & Imbalzano, A. Chromatin remodelling in mammalian differentiation: lessons from ATP-dependent remodellers. Nat Rev Genet 7, 461–473 (2006). https://doi.org/10.1038/nrg1882

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