Structural changes of chromatin, which consists of nucleosomes and nucleosome-associated factors, lead to functional changes
that are important determinants of eukaryotic gene regulation. These structural changes are regulated by modifications of histones and
DNA, both of which are components of nucleosomes, as well as by replacement of histone variants and the actions of noncoding RNAs.
In studies of chromatin modifications, a great deal of attention has been paid to histone acetylation. Progress in understanding this subject
has been extensive, including i) elucidation of the relationship of histone acetylation and gene activity; ii) the first isolation of a histonemodifying
enzyme; iii) the first identification of a factor that recognizes a modified site; iv) elucidation of the mechanism by which histone
modification leads to structural changes in nucleosomes; and v) elucidation of the mechanism of border formation between euchromatin
and heterochromatin. Histone acetylation is considered to be fundamental in several fields, including studies of a) the role of chromatin
and epigenetics in higher-order biochemical systems such as transcription, DNA replication, and repair; b) biological phenomena
such as cell proliferation and differentiation; and c) cancer and aging, potentially leading to clinical applications. In this review, I will
discuss the histone code hypothesis, at one time believed to represent a unified theory regarding the functions of histone modification. In
addition, I will describe the “modification web theory, ” by which the problems in the histone code hypothesis can be overcome, as well
as the “signal router theory, ” which explains the mechanisms of formation, development, and evolution of the modification web from a
structural viewpoint. Lastly, I will illustrate how these novel theories partially explain the robustness of biological systems against various
perturbations, and elucidate the strategy that a cell employs to avoid fatal fragility.