Trends in Genetics
Volume 27, Issue 10, October 2011, Pages 389-396
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Opinion
Histone modification: cause or cog?

https://doi.org/10.1016/j.tig.2011.06.006Get rights and content

Histone modifications are key components of chromatin packaging but whether they constitute a ‘code’ has been contested. We believe that the central issue is causality: are histone modifications responsible for differences between chromatin states, or are differences in modifications mostly consequences of dynamic processes, such as transcription and nucleosome remodeling? We find that inferences of causality are often based on correlation and that patterns of some key histone modifications are more easily explained as consequences of nucleosome disruption in the presence of histone modifying enzymes. We suggest that the 35-year-old DNA accessibility paradigm provides a mechanistically sound basis for understanding the role of nucleosomes in gene regulation and epigenetic inheritance. Based on this view, histone modifications and variants contribute to diversification of a chromatin landscape shaped by dynamic processes that are driven primarily by transcription and nucleosome remodeling.

Section snippets

An embroidery of chromatin modifications

There is general agreement in the chromatin field (see Glossary) that histone modifications play important roles in biological regulation. For example, acetylation of histone tails neutralizes the positive charge of lysines and profoundly alters chromatin properties 1, 2. Methylation of particular lysines on histone tails can increase the affinity of binding modules present on a variety of proteins that are thought to act by altering chromatin packaging [3]. Ancient roles for these and other

Do combinations of modifications dictate chromatin states?

At about the same time that a histone code was proposed to exist [4], genome-scale methods for mapping histone modifications were introduced 16, 17, and there are now dozens of ‘ChIP-chip’ and ‘ChIP-seq’ studies that profile histone modifications at an increasingly greater resolution and genome coverage 18, 19, 20, 21. When coupled with sophisticated computational techniques, these data sets can be used to predict sites of regulatory elements and the more data sets that are used, the more

The chromatin landscape is dynamic

Revolutionary technological advances in genomics over the past several years have begun to define the chromatin landscape at single nucleosome resolution, sometimes with single base-pair precision 18, 32. The picture that is emerging from these studies is that the chromatin landscape is more complex than the simple traditional concept of ‘open’ and ‘closed’ chromatin implies. In addition, progress in understanding the action of enzymes that act on chromatin, including ATP-dependent nucleosome

DNA accessibility as a paradigm for chromatin regulation

Nucleosomes block access of many DNA-binding proteins to their sites of action, and accessible regions are those that regulate gene expression, initiation of DNA replication origins and other DNA transactions. This concept was put forward by Weintraub and Groudine 35 years ago in their introduction of DNaseI hypersensitivity mapping [15], which is still a widely used method for determining sites of heightened steady-state accessibility of DNA to strand cleavage 41, 42. More recent high

Concluding remarks

Describing histone modifications in terms of information or language suggests overwhelming complexity and leaves mechanistic questions unaddressed. By contrast, DNA accessibility provides a simple testable paradigm for understanding the role of nucleosomes in gene regulatory processes. The view that emerges is that dynamic processes affecting nucleosomes result in patterns of histone modifications, which in turn affect the physical properties of nucleosomes and help to maintain the active or

Acknowledgments

This essay was conceived during the Keystone Symposium on ‘Histone code: fact or fiction?’, wherein we participated in the closing debate on the subject. We thank Bryan Turner, Barbara Panning and Alex Ruthenburg, who also participated in the debate, as well as meeting participants who chimed in during the discussion, for helping to clarify the issues. We also thank Mark Ptashne, Tim Bestor, Paul Talbert, Edwin Smith and anonymous reviewers for helpful comments on the manuscript.

Glossary

Chromatin
genomic DNA in its packaged form, consisting primarily of nucleosomes, but also including linker histones, DNA-binding proteins and other protein complexes directly or indirectly bound to nucleosomes or linker DNA.
Chromodomain
a protein module that has evolved to recognize a methylated lysine on a histone tail. For example, the HP1 chromodomain preferentially binds H3K9me with increasing affinity for mono- to di- to tri-methyl, whereas the Polycomb chromodomain preferentially binds

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