2.1 Structure and Function of Histones

2.1.1 Introduction to Histones

Histones are small, positively charged proteins that play a crucial role in packaging DNA within the nucleus. These proteins are essential for chromosome structure and gene regulation. In this section, you’ll learn about the different types of histones and their specific functions.

2.1.2 Types of Histones

There are five main types of histones:

1. H1 (linker histone)

2. H2A

3. H2B

4. H3

5. H4

Each type of histone has a unique structure and function within the chromatin.

2.1.3 Core Histones

H2A, H2B, H3, and H4 are known as core histones. These proteins form the central part of the nucleosome, which is the basic unit of chromatin. Core histones have a similar structure, consisting of:

• A globular domain

• A flexible N-terminal tail

• A C-terminal tail

The globular domain is involved in histone-histone and histone-DNA interactions, while the tails are sites for various post-translational modifications.

2.1.4 Linker Histone H1

H1 is different from the core histones. It binds to the DNA between nucleosomes and helps to stabilize higher-order chromatin structures. H1 plays a role in:

• Chromatin compaction

• Gene regulation

• DNA replication

• DNA repair

2.1.5 Histone Function

Histones serve several important functions:

1. DNA packaging: They help to compact DNA into a more manageable form within the nucleus.

2. Gene regulation: Histone modifications can affect gene expression by altering chromatin structure.

3. DNA protection: Histones shield DNA from damage caused by environmental factors.

4. Cell division: They play a role in chromosome condensation during mitosis and meiosis.

2.2 Assembly of DNA Around Histone Octamers

2.2.1 The Nucleosome Core Particle

The nucleosome core particle is the fundamental unit of chromatin. It consists of:

• 147 base pairs of DNA

• An octamer of core histones (two each of H2A, H2B, H3, and H4)

2.2.2 Histone Octamer Formation

The histone octamer forms in a step-wise manner:

1. Two H3-H4 dimers come together to form a tetramer.

2. Two H2A-H2B dimers then join the H3-H4 tetramer to complete the octamer.

2.2.3 DNA Wrapping

Once the histone octamer is formed, DNA wraps around it in a left-handed superhelix. This wrapping occurs in about 1.65 turns, creating the nucleosome core particle.

2.2.4 Linker DNA

The DNA between nucleosomes is called linker DNA. Its length varies between species and cell types, typically ranging from 20 to 90 base pairs.

2.3 Nucleosome Positioning and Its Significance

2.3.1 Factors Affecting Nucleosome Positioning

Several factors influence where nucleosomes are positioned along the DNA:

1. DNA sequence: Certain DNA sequences are more favorable for nucleosome formation.

2. DNA-binding proteins: Some proteins can compete with or recruit nucleosomes to specific sites.

3. ATP-dependent chromatin remodeling complexes: These complexes can move, remove, or restructure nucleosomes.

2.3.2 Significance of Nucleosome Positioning

The position of nucleosomes along the DNA has important implications for various cellular processes:

1. Gene regulation: Nucleosomes can block or allow access to regulatory DNA sequences.

2. DNA replication: Nucleosome positioning affects the initiation and progression of DNA replication.

3. DNA repair: The accessibility of DNA damage sites to repair machinery is influenced by nucleosome positioning.

4. Transcription: Nucleosomes can act as barriers to RNA polymerase progression.

2.3.3 Nucleosome-Free Regions

Certain areas of the genome, particularly around gene promoters and enhancers, tend to be depleted of nucleosomes. These nucleosome-free regions are often sites of active gene regulation.

2.4 Histone Modifications and Their Effects on Chromosome Structure

2.4.1 Types of Histone Modifications

Histones can undergo various post-translational modifications, including:

1. Acetylation

2. Methylation

3. Phosphorylation

4. Ubiquitination

5. Sumoylation

These modifications primarily occur on the N-terminal tails of histones, but some can also occur in the globular domains.

2.4.2 Histone Acetylation

Histone acetylation involves the addition of an acetyl group to lysine residues on histone tails. This modification:

• Neutralizes the positive charge of lysine

• Weakens histone-DNA interactions

• Generally promotes a more open chromatin structure

Histone acetylation is often associated with active gene transcription.

2.4.3 Histone Methylation

Histone methylation involves the addition of methyl groups to lysine or arginine residues. Unlike acetylation, methylation does not change the charge of the histone. The effects of histone methylation depend on:

• Which residue is methylated

• How many methyl groups are added (mono-, di-, or tri-methylation)

Some methylation marks are associated with active transcription, while others are linked to gene repression.

2.4.4 Other Histone Modifications

Phosphorylation, ubiquitination, and sumoylation also play important roles in regulating chromatin structure and function. For example:

• Histone phosphorylation is involved in DNA damage response and chromosome condensation during cell division.

• Histone ubiquitination can either activate or repress transcription, depending on the specific histone and residue modified.

2.4.5 The Histone Code Hypothesis

The histone code hypothesis suggests that specific combinations of histone modifications create binding sites for other proteins, which then carry out various functions on the chromatin. This concept helps explain how a relatively small number of modifications can lead to a wide range of chromatin states and gene expression patterns.

2.4.6 Effects on Chromosome Structure

Histone modifications can affect chromosome structure in several ways:

1. Altering histone-DNA interactions

2. Recruiting or repelling chromatin-binding proteins

3. Influencing higher-order chromatin structures

These changes in chromosome structure can have profound effects on gene expression, DNA replication, and other nuclear processes.