核心组蛋白乙酰化：动态的表观遗传密码

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"《组蛋白乙酰化与表观遗传密码》论文概述了在生物学领域的一项关键发现——组蛋白N-端尾部域的酶催化乙酰化是如何作为丰富的表观遗传信息来源的。这篇由Bryan M. Turner撰写的文章深入探讨了这一过程在调控基因表达中的作用。首先，组蛋白乙酰化是转录过程中的即时调节机制。通过改变启动子附近的核小体结构，它可以临时性地影响基因的开启或关闭。这涉及对特定氨基酸残基（如赖氨酸）的乙酰化，这些区域位于核心组蛋白上，对基因表达有着显著影响。更重要的是，长期来看，组蛋白乙酰化能够维护和调节基因表达模式。这种维持可能是通过在整个染色体区域设置特定的乙酰化模式来实现的，可能涉及到大面积的基因组区域。这涉及一组称为HATs（组蛋白乙酰转移酶）和HDACs（组蛋白去乙酰化酶）的蛋白质，它们可以精确地定位到基因组的特定部位，并表现出不同程度的选择性，这与它们在动态的乙酰化表观遗传编码中的角色相吻合。这个乙酰化代码并非孤立存在，而是通过非组蛋白蛋白质的乙酰化依赖结合或者直接作用于染色质结构来发挥作用。例如，一些蛋白质会识别并响应组蛋白的乙酰化状态，从而执行功能性的效应。近期的研究进一步提出，这种表观遗传机制可能与适应性进化、细胞分化以及疾病的发生发展紧密相关。组蛋白乙酰化作为表观遗传代码的关键组件，不仅在即时的基因调控中起着重要作用，而且通过动态维持和调节基因表达模式，为细胞生命过程中的各种复杂行为提供了精细的调控手段。理解这一机制对于解析生命过程中的可塑性和可遗传性变化具有重要意义，也为疾病的预防和治疗提供了新的视角。"

Histone acetylation and

an epigenetic code

Bryan M. Turner

Summary

The enzyme-catalyzed acetylation of the N-terminal tail

domains of core histones provides a rich potential

source of epigenetic information. This may be used both

to mediate transient changes in transcription, through

modification of promoter-proximal nucleosomes, and

for the longer-term maintenance and modulation of

patterns of gene expression. The latter may be achieved

by setting specific patterns of histone acetylation,

perhaps involving acetylation of particular lysine resi-

dues, across relatively large chromatin domains. The

histone acetylating and deacetylating enzymes (HATs

and HDACs, respectively) can be targeted to specific

regions of the genome and show varying degrees of

substrate specificity, properties that are consistent with

a role in maintaining a dynamic, acetylation-based

epigenetic code. The code may be read (ie. exert a

functional effect) either through non-histone proteins

that bind in an acetylation-dependent manner, or through

direct effects on chromatin structure. Recent evidence

raises the interesting possibility that an acetylation-

based code may operate through both mitosis and

meiosis, providing a possible mechanism for germ-line

transmission of epigenetic changes. BioEssays

22:836±845, 2000. ß 2000 John Wiley & Sons, Inc.

Introduction

A quarter of a century has passed since the nucleosome was

first recognised as the fundamental unit of chromatin

structure in eukaryotic cells. In this time, its perceived role

has expanded from a DNA-packaging element to a crucial

determinant of virtually all aspects of genomic function.

(1)

The isolated nucleosome core particle comprises a histone

octamer, two copies each of H2A, H2B, H3 and H4, around

which is wrapped 146 base pairs of DNA. This structure is

the same in virtually all eukaryotes. However, in vivo this

extremely conserved structure is subject to numerous

enzyme-catalyzed manipulations and modifications that give

it an almost infinite capacity for variability. A major contributor

to this heterogeneity is the enzyme-catalyzed, post-transla-

tional modification of the N-terminal tails of the eight core

histones. The tails are exposed on the nucleosome surface

and can be modified by acetylation, phosphorylation,

methylation, ubiquitination and ADP-ribosylation of specific

amino acids.

(2)

Of these modifications, acetylation of the e-

amino group of defined lysine residues is the most frequently

occurring and extensively studied.

Any discussion of the possible functions of histone

modification must take account of the fact that the nucleo-

some is involved, one way or another, in virtually every

activity of nuclear DNA, including transcription, replication

and repair. It is difficult, possibly unwise, to consider these

activities in isolation. With this in mind, this review will focus

on an aspect of the subject that has received, till recently,

relatively little attention. It will explore the possibility that

histone modifications provide a mechanism for encoding and

transmitting information about genomic function from one cell

generation to the next; in other words, an epigenetic code. In

what follows, histone acetylation will provide most of the

experimental examples, but the possibilities discussed may

equally well be applied to other modifications whose analysis

is still at a relatively early stage. In fact, it is becoming

increasingly clear that important functional effects can

depend on precise combinations of modifications.

Finding coded messages

The idea that chromatin in general and patterns of histone

acetylation in particular may constitute a code that transmits

epigenetic information has been suggested before

(3±8)

, but

recent experiments have provided valuable insights into the

nature of the putative code and how it might operate. There

are several examples, some long standing, of specific

modifications that are associated with defined functional

effects. These are listed in Table 1. The potential importance

of combinations of modified residues has been emphasized

more recently by studies of phosphorylation of H3 serine10.

This residue is phosphorylated at high frequency as cells

836 BioEssays 22.9 BioEssays 22:836±845, ß 2000 John Wiley & Sons, Inc.

Chromatin and Gene Expression Group, Anatomy Department

University of Birmingham Medical School, Birmingham B15 2TT, UK.

E-mail: b.m.turner@bham.ac.uk

Abbreviations: ChIP, Chromatin ImmunPrecipitation; Fab-7, Droso-

phila DNA sequence that can activate and suppress transcription in

cis; H4Ac5 (8,12,16), Histone H4 acetylated at lysine residue 5

(8,12,16); HAT, Histone AcetylTransferase; HDAC, Histone Deacety-

lase; MBD2, Methyl Binding Domain protein 2; MeCP2, Methyl CpG-

binding Protein 2; MOF, Drosophila histone acetyltransferase named

after its mutant phenotype and chromosome location (Males-absent

On the First); Rpd3p, An important yeast transcriptional regulator and

histone deacetylase; SAGA, Yeast acetyltransferase complex named

after some of its constituent proteins; white, Drosophila gene whose

activity is necessary for the red eye colour of wild-type flies; its

mutation gives a white-eyed phenotype.

Problems and paradigms

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