Escs Keep Their Options Open
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RESEARCH HIGHLIGHTS CHROMATIN TECHNIQUES ESCs keep their options open 1 1 1 Two powerful technologies enabled studies ESC HSC T Phase genes were late-replicating, which is charac- methods Cripto G1 S1 S2 S3 S4 G2 of chromatin that revealed features poten- Esg1 teristic of silenced chromatin. The authors tially responsible for the pluripotency of Fgf4 suggest that this is indicative of a difference Foxd3 embryonic stem cells (ESCs). Nanog in transcriptional ‘competence’ and is a mark Oct4 Various studies have suggested that the Rex1 of lineage state. .com/nature e pattern of epigenetic modification may Utf1 They observed concomitant H3Lys4 and mark a cell’s developmental stage. There are H3Lys27 methylation, and were encouraged .natur Figure 1 | Replication-timing analysis of ESCs, many modifications that modulate chroma- that Bernstein et al. also observed this sur- w HSCs and T lymphocytes according to the extent of tin structure; among them are methylation replication during G1, G2 and throughout S phase. prising combination at other developmental of histone H3 lysine 4 (H3Lys4) and lysine Reprinted with permission from Nature Cell Biology. genes. “So these two papers really comple- 27 (H3Lys27), which regulate transcription mented each other, and gave you this idea http://ww positively and negatively, respectively. that you might have a significant compo- oup To study the pattern of histone modifi- helped push the biology, helped us see this nent of the genome being primed and ready r G cation, Bradley Bernstein of Massachusetts unique pattern, and also believe it because we to go in [ESCs] but being held in check by General Hospital, Harvard Medical School saw it again and again.” The authors suggest [H3Lys27] methylation,” says Fisher. She and the Broad Institute, and his colleagues that these bivalent domains silence genes in added that it is likely that somatic stem cells lishing carried out chromatin immunoprecipitation ESCs while keeping them poised for selective may use a similar mechanism to keep a subset b (ChIP) with antibodies against methylated activation during differentiation. of lineage options available, but not active, Pu H3Lys4 or H3Lys27, and then used tiling Addressing similar questions, a team led and she expects to see papers in the near arrays to analyze larger regions of the genome by Amanda Fisher and Véronique Azuara future describing similar epigenetic patterns Nature than was previously possible. Bernstein of the UK Medical Research Council at the in different somatic stem cells. 6 explains: “Tiling arrays are unique in that Imperial College School of Medicine com- The exciting findings described in these 200 rather than focusing on a particular genomic pared epigenetic profiles of ESCs, hemato- two articles were possible because of the © feature like a gene, exon or even a promoter, poietic stem cells (HSCs) and differentiated recent development of microarray tiling [they] cover the entire unique sequence of, T lymphocytes, hoping to find epigenetic fea- technology, which allowed analysis of a for example, a chromosome.” Prior work tures that distinguish pluripotent cells from large genomic space, and the availability of had revealed that modifications generally those with more restricted developmental sophisticated cell sorters to obtain sufficient affected short stretches of DNA, but at some potential (Azuara et al., 2006). According to amounts of cell subpopulations for analysis genes encoding developmentally important Azuara, they began this study “with the idea without the need to arrest cells with drugs. transcription factors, larger regions of tens of that cell identity could be defined by genes Fisher emphasized that these new technolo- kilobases contained modified histones. being repressed rather than genes being gies have revolutionized this area, and “as Bernstein and colleagues found that large active. So when you are an [ESC], you would more people can get their hands on top-of- regions of modified histones appear to be keep the potential to express any of the genes, the-range FACS sorting and custom-made a general feature of loci containing ‘devel- but when you become a lymphocyte, maybe arrays, then progress could be much faster.” opmental’ genes (Bernstein et al., 2006). In you are identified by the fact that you can’t Bernstein echoes the idea that forthcom- differentiated cells these regions were either express some genes.” ing technological advances will allow global transcriptionally active or silent⎯methylated The UK researchers performed replication- analyses and adds, “I think as that progresses, at H3Lys4 or H3Lys27, respectively. In ESCs, timing analysis, which allows identification of we are just going to become exponentially however, the developmental genes were accessible chromatin that is characterized by more informed about the epigenetic mecha- marked by ‘bivalent domains’ comprising early replication during S phase. Briefly, they nisms that regulate development and about large regions of H3Lys27 methylation harbor- pulse-labeled DNA of cell populations, frac- how aberrant epigenetic regulation can lead ing smaller regions of H3Lys4 methylation, tionated the cells according to cell-cycle stage to cancer and other diseases.” modifications that were thought to be mutu- and determined the presence of developmen- Irene Kaganman ally exclusive. “We might not have believed tal genes in the labeled DNA by PCR at each RESEARCH PAPERS this,” says Bernstein, but he points out that stage (Fig. 1). They found that in ESCs many Azuara, V. et al. Chromatin signatures of pluripotent they used a tiled array that contained 60 Mb developmentally important genes replicated cell lines. Nat. Cell Biol. 8, 532–538 (2006). Bernstein, B.E. et al. A bivalent chromatin structure of genome and saw this methylation pattern early but were not expressed; in HSCs and marks key developmental genes in embryonic stem repeatedly. “So that is the way that technology differentiated T lymphocytes some of these cells. Cell 125, 315−326 (2006). NATURE METHODS | VOL.3 NO.6 | JUNE 2006 | 419.