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Protein modules that manipulate histone tails for chromatin regulation

Nature Reviews Molecular Cell Biology volume 2, pages 422–432 (2001)Cite this article

Key Points

  • Chromatin is composed of nucleosomes, which consist of DNA and histone proteins. The histone amino terminus has a 'tail' region that is highly conserved between species and consists of protein modules that are responsible for post-translational modification of histones.

  • Many histone modifications take place in the form of acetylation, methylation or phosphorylation, and have been correlated with nuclear activities such as replication, chromatin assembly and transcription. It is thought that modification of histones is a sequential or combinatorial process such that a 'histone code' materializes which promotes transcriptional events downstream.

  • Histone acetylation/deacetylation is the most studied histone modification activity. It is correlated with transcriptional activation/repression. The enzymes that mediate this process are histone acetyltransferases (HATs) and histone deacetylases (HDACs). Bromodomain and kinase domain modules can act as transcriptional coactivators by aiding the process to proceed. There are distinct functional links between HATs/HDACs and these modules.

  • Gene silencing occurs during the formation of higher-order heterochromatin through histone methylation. This process is aided by SET domains and chromodomains.

  • Other conserved protein modules involved in histone modification are also known, although their biochemical functions are as yet poorly defined. Of those modules that have been studied extensively, it is still not entirely clear what the function of these modules is or in what sequence they interact with histone tails to coordinate and regulate gene expression. Futher studies will concentrate on these issues.

Abstract

Histones are the predominant protein components of chromatin and are subject to specific post-translational modifications that are correlated with transcriptional competence. Among these histone modifications are acetylation, phosphorylation and methylation, and recent studies reveal that conserved protein modules mediate the attachment, removal or recognition of these modifications. It is becoming clear that appropriate coordination of histone modifications and their manipulations by conserved protein modules are integral to gene-specific transcriptional regulation within chromatin.

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Figure 1: Chromatin organization and the histone H3 amino-terminal tail.
Figure 2: Chromatin-regulatory proteins and their associated modules.
Figure 3: Overall structure of HAT domain module.
Figure 4: Structure of the bromodomain module.
Figure 5: Model for cooperation of the HAT, kinase and bromodomain modules for transcriptional activation.
Figure 6: Structure of the chromodomain module.

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Authors and Affiliations

  1. The Wistar Institute and the Department of Chemistry, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Ronen Marmorstein

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  1. Ronen Marmorstein
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DATABASE LINKS

H2A

H2B

H3

H4

H1

RNA polymerase II

TATA binding protein

Gcn5

HAT

Ada

N-CoR

SMRT

HDACs

Protein Data Bank

CREB

CBP

p300

TAFII250

PCAF

TAFII130

Moz

Sas3

Sas2

Tip60

Esa1

BRG1

Swi2

Sth1

Bdf1

c-fos

c-jun

EGF

HP1

SUV39H1

Suv39hl

Su(var)205

Clr4

Swi6

Clr3

M33

Mi-2

MOF

Mod1

CARM-1

GRIP1

PRMT1

RING

E3 ubiquitin ligase

Swi3

Ada2

TFIIIB B

Glossary

NUCLEAR HORMONE RECEPTOR COREPRESSORS

Proteins that interact with DNA-bound nuclear hormone receptors to facilitate the repression of gene expression.

HETEROCHROMATIN

A highly condensed form of chromatin that occurs at defined sites, such as silencer DNA elements or telomeres.

BROMODOMAIN

A domain with sequence conservation that is found in several transcriptional regulatory proteins involved in gene activation, and contains acetyl-lysine binding activity.

IPL1/AURORA KINASES

A family of homologous kinases in which histone H3 kinase activity is correlated with chromosome condensation.

TELOMERES

The ends of eukaryotic chromosomes.

EUCHROMATIC

DNA that contains most of the structural genes, changes structure during the cell cycle and undergoes transcriptional regulation.

MATING TYPE LOCI

Gene regulatory regions of the yeast chromosome that control the sexual fate of the yeast cell.

CHROMODOMAIN

A domain with sequence conservation that is found in several transcriptional regulatory proteins. The chromodomain from HP1 has been shown to contain methyl-lysine-binding activity.

DOSAGE COMPENSATION

A process in organisms that have male and female sexes, which ensures that different copies of the sex chromosome between these sexes have the same amount of most of the sex chromosome gene products.

HISTONE FOLD

Refers to proteins that contain the same tertiary structure as the core region of the core histones.

CHROMOSHADOW DOMAIN

A domain in HP1 that is highly related in sequence and structure to the chromodomain. Unlike the chromodomain, which is monomeric, the chromoshadow domain is dimeric.

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Marmorstein, R. Protein modules that manipulate histone tails for chromatin regulation. Nat Rev Mol Cell Biol 2, 422–432 (2001). https://doi.org/10.1038/35073047

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