Chromatin remodelling during development

Abstract

New methods for the genome-wide analysis of chromatin are providing insight into its roles in development and their underlying mechanisms. Current studies indicate that chromatin is dynamic, with its structure and its histone modifications undergoing global changes during transitions in development and in response to extracellular cues. In addition to DNA methylation and histone modification, ATP-dependent enzymes that remodel chromatin are important controllers of chromatin structure and assembly, and are major contributors to the dynamic nature of chromatin. Evidence is emerging that these chromatin-remodelling enzymes have instructive and programmatic roles during development. Particularly intriguing are the findings that specialized assemblies of ATP-dependent remodellers are essential for establishing and maintaining pluripotent and multipotent states in cells.

Figure 1. Combinatorial assembly of chromatin-remodelling complexes produces biological specificity

Brahma-associated factor (BAF) complexes (a) and nucleosome-remodelling and histone deacetylase (NURD) complexes (b). Analogous subunits of each complex are shown as similar shapes in the same colour, allowing them to occupy specific positions in the illustration of the complex, as in a jigsaw puzzle. The colour schemes in a and b are unrelated. The domains that enable the subunits to interact with DNA are depicted at the surface of each protein, as explained in the key. a, Tissue-type-specific and cell-type-specific assemblies of BAF complexes (which are members of the SWI/SNF family of chromatin-remodelling complexes) have distinct functions that are indispensable to their resident cell type. The diagram depicts the composition of BAF complexes in some of the primary cell types that have been characterized so far. In each case, the subunits shown are stable members of the complex; in some cases, they have been shown to be non-exchangeable in experimental challenges with an in vitro-synthesized subunit. The possible subunits at each position are listed (for example, BAF60A, B indicates that one of these two subunits is present). For subunits labelled with a question mark, it is unclear which family member is present at that position. The variable subunits that distinguish the complexes depicted here are highlighted in boldface type: these are the core ATPase (brahma-related gene 1 (BRG1) or brahma (BRM)), BAF45, BAF53, BAF60 and BAF155 and/or BAF170. The BAF complex in embryonic stem cells (ESCs) is called esBAF; in neuronal progenitors, npBAF; and in neurons, nBAF. In cardiac progenitors, the composition of the BAF complex is also distinct but has not been characterized by proteomic analysis, unlike the other BAF complexes shown. In the respective cell types, these complexes have been experimentally shown to mediate specific processes (which are listed below each complex) that cannot be mediated by BAF complexes of other compositions. In some cases, key transcription factors that work in cooperation with BAF complexes (such as OCT4 and SOX2 in ESCs, CREST in neurons and GATA4 and TBX5 in cardiac progenitors) are depicted. These transiently associated transcription factors are not shown in contact with the main complex to distinguish them from the subunits of the complex. b, NURD complexes (which are members of the CHD family of chromatin-remodelling complexes) incorporate different products of the MTA (metastasis-associated) gene family, and these complexes have distinct, and even opposing, functions in regulating the development and tumorigenesis of mammary tissues (see ref. for a review). For example, MTA1-containing complexes repress oestrogen-receptor-mediated transcription and thereby contribute to the invasive growth of cancerous mammary tissue. By contrast, MTA3-containing complexes interact with BCL6 and directly repress the expression of metastasis-inducing gene Snail (also known as Snai1), thereby contributing to the maintenance of a non-invasive mammary phenotype. BAF200, also known as ARID1; BAF250, also known as ARID2; BRD, bromodomain-containing protein; HDAC, histone deacetylase; MBD, methyl-CpG-binding domain; PHD, plant homeodomain; RbBP, retinoblastoma-associated-binding protein.

Figure 2. Chromatin-remodelling complexes in development

The four families of chromatin remodellers — SWI/SNF (green background), ISWI (yellow), CHD (orange) and INO80 (pink) — are required at distinct steps for the normal development of the development of embryos (implantation, gastrulation and organogenesis) and for the formation of gametes. The proteins known to be involved in mouse development are listed next to each step, together with the family of the complex involved (and the name of the specific complex, in parentheses, if known). In cases in which studies using mouse models have not been reported, proteins found to be involved in Drosophila melanogaster development are listed, as denoted by (D), although it is unclear whether these results can be extrapolated to mammalian development. BAF complexes are involved in most of the developmental transitions depicted. The requirement for BAF complexes throughout development could reflect the many combinatorial possibilities of BAF complex composition. However, the apparent involvement of BAF complexes more than other chromatin-remodelling complexes could just reflect that these complexes are the most widely studied of the chromatin remodellers. BAP, Brahma-associated proteins; BPTF, bromodomain PHD-finger transcription factor; CERF, CECR2-containing remodelling factor; CNS, central nervous system; ICM, inner cell mass; MOR, Moira; NURF, nucleosome-remodelling factor; SNR1, Snf5-related protein 1; TRRAP, transformation/transcription-domain-associated protein.

Figure 3. Chromatin-remodelling complexes in maintaining pluripotency

ESCs are characterized by hyperdynamic chromatin, which is compacted when these cells exit from their pluripotent state and differentiate into cells of multiple lineages. In the self-renewing state, chromatin remodellers are required to prevent this chromatin compaction (CHD1) and to repress and refine the inappropriate expression of genes (esBAF and the TIP60-p400 complex) that would otherwise be allowed by the permissive chromatin landscape. Exit from this self-renewing state into a state that allows multilineage commitment involves global changes in chromatin configuration, such as the formation of heterochromatin and the silencing of pluripotency genes (BAF complexes and NURD complexes), and key signalling events (bone-morphogenetic-protein-mediated signalling pathway and NURF complexes). Not surprisingly, evidence is emerging that chromatin remodellers such as BAF complexes (by way of an unknown mechanism) are crucial for the reversal of development and the reactivation of pluripotency genes such as Oct4, which occurs during the nuclear reprogramming of a committed cell type back into an ESC-like state. The proteins known to be involved are listed, together with the chromatin-remodelling complex they are found in (CHD, orange; SWI/SNF, green; ISWI, yellow; and INO80, pink).