Unraveling the score of the enhancer symphony.

O ne of the most fascinating and daunting challenges of contemporary developmental biology is to fully classify diverse cell types on the basis of a quantifiable genetic profile. Although compiling an inventory of such identifying features seems feasible for some specific cell types (e.g., those of the hematopoietic system), a robust and universal platform has yet to emerge. Indeed, in most cases, a series of confirmatory physiological assays are still needed to verify cell identity, yet such assays are available for only a small subset of classifiable cells and can be quite difficult to conduct and interpret. A study by Creyghton et al. (1) provides a possible solution to this conundrum. It gives us a first and unique glimpse of the regulatory complexity of enhancers at the epigenetic level and suggests that histone marks allow discrimination between at least two kinds of enhancers: those that are truly active and whose activities correlate closely and specifically with cell identity and those that are poised to engage in future enhancer activity, thus allowing predictions about the lineage decisions that the cell is facing. Over the last 5–10 y, it has been become apparent that specific combinations of epigenetic marks may provide a muchneeded bar code specific to a given cell type. Epigenetic features such as covalent histone tail modifications seem especially useful in this context, because they (i) are typically transmitted very faithfully fromone cell generation to the next, (ii) are imposed and removed in a highly dynamic fashion, and (iii) allow storage of information at relatively high densities. Although early studies emphasized the histonemarks found within promoter regions, it has become clear that histone modifications closely linked to distal enhancers can provide stunningly accurate predictions of lineage specification (2–6). This is not surprising at all, because enhancer elements have long been considered key to highly modular patterns of specific gene expression. Indeed, the cross-talk between promoters and enhancer elements is the subject of much recent intensive research (7). Although systematic cataloging of enhancers based on DNA sequence information has proven difficult, in part because such elements do not always display the necessary level of DNA conservation needed for such analyses (2), specific histone marks (monomethylation of lysine 4 of histone H3 or H3K4me1 and acetylation of lysine 27 on the same histone or H3K27ac) have become extraordinarily useful surrogate markers for identifying enhancers. The success of this method is well illustrated by the ability of an H3K4me1-based system to enablemapping of all enhancers in any given cell, irrespective of the activity of the enhancer (over 10–10 enhancers have been mapped to date) (8). However, such knowledge, although impressive, does little to clarify the current and future developmental potential of the cell. To draw an analogy from the world of symphony music, one