Nucleo

REVIEWS

NUCLEAR COMPARTMENTALIZATION AND GENE ACTIVITY
Claire Francastel*, Dirk Schübeler*, David I. K. Martin‡ and Mark Groudine*§
The regulated expression of genes during development and differentiation is influenced by the availability of regulatory proteins and accessibility of the DNA to the transcriptional apparatus. There is growing evidence that the transcriptional activity of genesis influenced by nuclear organization, which itself changes during differentiation. How do these changes in nuclear organization help to establish specific patterns of gene expression?

HETEROCHROMATIN

A condensed form of chromatin; the degree of compaction is similar to that of mitotic chromosomes. It is usually found around the centromere.
INTERPHASE

The period between two mitoticdivisions.

Cellular differentiation is the process by which a cell acquires a new phenotype to accomplish specific functions, and it is accompanied by activation of a specific subset of genes and silencing of the remainder. As genes are silenced, the extent of chromatin condensation increases, and extended regions of DNA are packaged in a transcriptionally inactive form often referred to as 1HETEROCHROMATIN . The amount and distribution of condensed chromatin is similar in terminally differentiated cells of the same lineage, but it varies in the nuclei of different cell types, indicating that nuclear organization may be cell-type specific2 (FIG. 1).

These observations have led to the idea that the topological organization of the INTERPHASE nucleus is related to the differentiatedstate of the cell, and that this spatial organization is involved in the establishment of the tissue-specific pattern of gene expression during cellular differentiation. Clearly, many overlapping pathways are involved in regulating gene expression3–6. Much research is focused on determining the proteins (trans-acting factors) and DNA sequences (cis-acting elements) involved in the dynamiclocalization of genes within the nucleus, and we are just beginning to understand the link between the structure and

*Fred Hutchinson Cancer Research Center, 1,100 Fairview Avenue North, Seattle, Washington 98109, USA. ‡The Victor Chang Cardiac Research Institute, 384 Victoria Street Darlinghurst, Sydney, New South Wales 2010, Australia. §Department of Radiation Oncology, University of Washington Schoolof Medicine, Seattle, Washington 98195, USA. Correspondence to M.G. e-mail: markg@fhcrc.org

Figure 1 | Patterns of chromatin condensation in haematopoietic cells. The electron micrographs show haematopoietic cells from normal human bone marrow82, and illustrate the distinct patterns of chromatin condensation in distinct terminally differentiated cells. a | Proerythroblast (immature red bloodcell). The nucleus contains almost no heterochromatin. b | Late erythroblast. Heterochromatin in the nucleus is predominant and appears as darkly staining regions. c | The nucleus of a monocyte (right) appears less condensed than that of a granulocyte (left). (Figure adapted with permission from REF. 82 © Harcourt Brace, Madrid, Spain.)

NATURE REVIEWS | MOLECUL AR CELL BIOLOGY

VOLUME 1 |NOVEMBER 2000 | 1 3 7

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REVIEWS
study the putative coupling of chromatin condensation and gene repression during the differentiation of somatic cells. The haematopoietic programme is initiated from a stem cell with self-renewal and differentiation capacities, which can give rise to several distinct lineages. In multipotent haematopoietic stem cells, many genesrelevant to different lineage fates are transcribed before the decision to commit to any one lineage8,9. In other words, before the commitment decision, a general ‘permissive’ state exists in which genes specific to several lineages may be in an open chromatin configuration. Moreover, the subsequent activation of genes for any one lineage is probably coincident with closing of those gene domains...