ScienceWeek

GENOME BIOLOGY: ON HISTONE MODIFICATIONS

The following points are made by W. Fischle et al (Nature 2003 425:475):

1) Inside a eukaryotic cell nucleus, chromatin is far more than a static carrier of the genetic information encoded in DNA, as it actively mediates dynamic changes in gene function and expression(1). The chromatin polymer integrates a variety of endogenous and exogenous signals and functions as a biological relay station and signalling platform(2). Emerging evidence suggests that covalent post-translational modifications of histones -- the main protein component of chromatin -- play key roles in controlling the capacity of the genome to store, release and inherit biological information.

2) Histone modifications can be highly reversible, such as histone (lysine) acetylation and histone (serine and threonine) phosphorylation, or more stable, such as histone (lysine and arginine) methylation(3,4). Thus, a wide range of histone- and chromatin-based regulatory options is available. These include rapid adjustments of gene expression in response to physiological and environmental stimuli as well as more permanent indexing systems, which could be involved in transmitting inheritable expression patterns from one cell generation to the next. Such inheritable changes in gene function and expression that do not involve changes in DNA sequence are commonly referred to as "epigenetic".

3) Fundamental cellular mechanisms uncovered in classical signalling pathways are manifested in the genetic and epigenetic regulatory circuits that control the post-translational modification of histones. For example, certain histone modifications (single sites of modification are referred to as "marks") recruit binding/effector proteins (referred to as "modules") -- a general biological principle initially established in phosphorylation-dependent signalling cascades(5). Also, some histone modifications appear to act redundantly, a phenomenon that has been observed in several biological systems that rely on a multitude of singular post-translational modifications to achieve a robust signal. However, other aspects of histone and chromatin biology appear to be more complex and are less clear.

4) In summary: An immense number of post-translational modifications on histone proteins have been described and additional sites of modification are still being uncovered. Whereas many direct and indirect connections between certain histone modifications and distinct biological phenomena have now been established, concepts for comprehending the extreme density and variety of these covalent modifications are lacking. The authors formally introduce localized "binary switches" and "modification cassettes" as new concepts in histone biology, elucidating mechanisms that might govern the biological readout of distinct modification patterns. The authors suggest their hypotheses provide missing models for the dynamic readout of stable histone modifications and offer explanations for several long-standing questions embedded in the literature. The authors suggest their ideas might also apply to non-histone proteins and are open to direct experimental examination.

References (abridged):

1. Felsenfeld, G. & Groudine, M. Controlling the double helix. Nature 421, 448-453 (2003)

2. Cheung, P., Allis, C. D. & Sassone-Corsi, P. Signaling to chromatin through histone modifications. Cell 103, 263-271 (2000)

3. Zhang, Y. & Reinberg, D. Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev. 15, 2343-2360 (2001)

4. Lachner, M. & Jenuwein, T. The many faces of histone lysine methylation. Curr. Opin. Cell Biol. 14, 286-298 (2002)

5. Pawson, T., Gish, G. D. & Nash, P. SH2 domains, interaction modules and cellular wiring. Trends Cell Biol. 11, 504-511 (2001)

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