Histone modifications: Combinatorial complexity or cumulative simplicity?

Posttranslational modifications of histones have attracted enduring interest ever since it was realized that histones are hyper-acetylated on lysines at actively transcribed genes (1). Because it neutralizes the charge on a lysine, acetylation was thought to reduce interactions with DNA phosphates, making the DNA more accessible for active processes such as transcription (2). In recent years, this simple charge neutralization model has been succeeded by a complex alternative: the histone code, in which combinations of different histone modifications specify alternative chromatin states (3). In this issue of PNAS, Dion et al. (4) present a critical test of these competing models. The concept of a histone code was introduced in the early 1990s by Turner (5), based on seminal studies of the involvement of histone lysine acetylation in a dosage compensation process. In flies, histone H4 is hyperacetylated on lysine-16 (K16) on the male, but not the female, X chromosome, a feature that was later shown to be instrumental in the process whereby the male X chromosome is 2-fold up-regulated to compensate for being hemizygous (6). Thus, H4 K16 appears to be dedicated to the process of X chromosome dosage compensation in Drosophila. The subsequent discovery that histone acetyltransferases and deacetylases are components of activator or repressor complexes (7), and the realization that histone methyltransferases provide potentially enormous combinatorial complexity (8), led to elaborations of Turner's original concept and considerable excitement in the chromatin field. One would think that an abundance of evidence underlies this paradigm shift from a model based on structural properties to an information-based code. However, experiments claimed to support the histone code hypothesis might also be accommodated by structural alternatives. For example, histone H3 K9 methylation is regarded as an epigenetic “mark” for heterochromatin because it provides a platform for binding by heterochromatin-associated protein 1 (HP-1) …