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  • Review Article
  • Published:

Haematopoietic cell-fate decisions, chromatin regulation and ikaros

Nature Reviews Immunology volume 2, pages 162–174 (2002)Cite this article

Key Points

  • Heritable chromatin modifications have been described for both DNA and histones. Although our knowledge of DNA modifications is limited to methylation of CpG islands, a range of histone modifications is being revealed as 'codes' that determine chromatin activity.

  • Histone codes can have direct effects on chromatin accessibility and they also provide additional layers of regulation through their interactions with other chromatin regulating factors. This provides an ingenious way to convey genetic information in a lineage-specific manner — information that is required not only to initiate but also to maintain the differentiated state.

  • The activity of ATP-dependent remodellers is crucial in this series of chromatin regulatory events. Remodellers are powerful ATP-driven enzymatic machines that can alter chromatin structure irrespective of its configuration and thereby provide transient access to chromatin modifiers. This might trigger a series of chromatin regulatory events that underlie changes in gene expression required for lineage decisions.

  • Ikaros is a lineage-regulating factor in the haematopoietic system. Lack of Ikaros impairs the production of lymphocyte progenitors/precursors and increases the production of their myeloid counterparts. In addition to an early role in lympho-myeloid cell-fate decisions, Ikaros seems to influence the outcome at a range of branch points of the lymphoid and myeloid pathways.

  • An important mechanism of Ikaros action involves chromatin remodelling. In fact, Ikaros is an integral component of a 2-MDa complex containing both chromatin remodelling and modifying activities. The Ikaros–NURD (nucleosome remodelling and histone deacetylation) complex and its associated activities can trigger a series of chromatin regulatory events by providing accessibility to lineage-determining factors and their chromatin-modifying associates. In this way, Ikaros might support one of two alternative fates in differentiation by potentiating the required events in gene expression.

  • The ability of Ikaros to target genes and nuclear compartments in a sequence-specific manner argues the case for gene-specific and global effects on chromatin regulation.

Abstract

The regulated production of several terminally differentiated cell types of the blood and immune systems (haematopoiesis) has been the focus of many studies on cell-fate determination. Chromatin and the control of its structure have been implicated in the regulation of cell-fate decisions and in the maintenance of the determined states. Here, I review advances in the field, emphasizing the potential role of chromatin in lineage commitment and differentiation. In this context, I discuss Ikaros, an essential regulator of lymphocyte development and an integral component of a functionally diverse chromatin remodelling network that operates from the early stages of haematopoiesis to the mature lymphocytes.

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Figure 1: Structure of a nucleosome.
Figure 2: Histone modifications as chromatin codes.
Figure 3: Models for the generation and propagation of histone codes.
Figure 4: Deciphering the histone code.
Figure 5: A model of how histone codes can influence lineage decisions.
Figure 6: Chromatin remodellers in the generation of histone code during development.
Figure 7: The most full-length Ikaros isoform (Ik-1) and its functional domains.
Figure 8: Gene-specific and global targeting of chromatin remodelling by Ikaros.

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Acknowledgements

I am grateful to members of my laboratory and to D. Kioussis for allowing me to cite unpublished results. I am indebted to J. Koipally, E. Wong, B. Heller, T. Yoshida and B. Morgan for constructive discussions and other support that helped to shape this manuscript.

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Authors and Affiliations

  1. CBRC, MGH East, 13th St, Charlestown, 02129, Massachusetts, USA

    Katia Georgopoulos

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  1. Katia Georgopoulos
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DATABASES

LocusLink

CD4

CD8

c-kit

DNMT3b

FLK2

GM-CSFR

GR1

HDAC1

HDAC2

HP1

Hunchback

Ikaros

IL-2 receptor-β

interferon-γ

interleukin 4

L-selectin

MBD3

Mi-2β

MTA2

Pegasus

Sin3

SUV39H1

TAFII250

 OMIM

tricho-rhino-phalangeal syndrome 1

Glossary

EPIGENETICS

The study of heritable changes in gene expression that occur without a change in DNA sequence.

CHROMATIN REMODELLING

A reversible alteration of chromatin structure mediated by ATP-dependent helicases, such as Mi-2 (NURD) and Brg1/Brm (SWI/SNF) that have an impact on several molecular processes, such as recombination, repair and transcription.

HETEROCHROMATIN

Highly compacted chromatin that is found constitutively in regions such as the centromere and telomere, and is mostly associated with transcriptionally silent genes. It is rich in A+T sequences and can therefore be visualized microscopically by staining of nuclei with DNA-intercalating dyes.

CHROMATIN CODE

A covalent modification on histones and DNA. They occur in different regions of the genome by enzymes such as acetylases, methylases and kinases, and result in alterations of gene transactions in a cell. These could include, for example, changes in transcription, recombination, timing of DNA replication and the degree of compaction of DNA.

CHROMODOMAIN

The chromatin organization modifier domain is an ∼50 amino-acid motif originally identified as a region of homology shared between the Drosophila Hp1 and Polycomb proteins, and that is now known to exist in plants and animals. Chromodomain-containing proteins are usually components of chromatin remodelling complexes and are also presumed to have a role in genome organization.

BROMODOMAIN

A 120-bp motif found in a variety of proteins, including histone acetyltranferases, kinases, basal transcription factors (TAFII250) and chromatin remodelling factors.

PERICENTROMERIC HETEROCHROMATIN

The heterochromatic regions surrounding centromeres that are postulated to be a site of recruitment of transcriptionally silent genes.

PRIMITIVE HAEMATOPOIESIS

The transient production of large, nucleated erythrocytes that express embryonic haemoglobin, which takes place in the yolk sac. Primitive megakaryocytopoiesis is also reported, but no other types of blood cell have ever been reported to be generated in primitive haematopoiesis.

DEFINITIVE HAEMATOPOIESIS

Haematopoiesis from pluripotent haematopoietic stem cells (HSCs), in which all types of blood cell are produced. HSCs emerge first in the aorta–gonad–mesonephros region, whereas the main sites of definitive haematopoiesis in fetuses and adults are the liver and bone marrow, respectively.

SPLANCHNOPLEURA

The layer formed by the union of splanchnic mesoderm and endoderm that gives rise to muscle, digestive tract and yolk sac.

POSITION EFFECT VARIEGATION

Stochastic silencing of a gene that is adjacent to heterochromatin in a proportion of cells.

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Georgopoulos, K. Haematopoietic cell-fate decisions, chromatin regulation and ikaros. Nat Rev Immunol 2, 162–174 (2002). https://doi.org/10.1038/nri747

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