5.12
Histon-modificatie
De histoneiwitten hebben een flexibele N-terminale staart die zich uitstrekt vanaf het nucleosoom. Deze histonstaarten worden vaak onderworpen aan pos…
A nucleosome contains a protein core that is made up of four histone core proteins: H2A, H2B, H3, and H4.
In addition to these four standard core histones, eukaryotes also possess a few variants of each histone, with the exception of H4.
The amino-terminal tails of the core standard and variant core histones protrude from the nucleosomes and are highly unstructured and mobile.
These tails, comprising of about 30 amino acids, are subjected to several forms of covalent modifications such as the acetylation of lysines, phosphorylation of serines, and mono-, di-, or tri-methylation of lysines.
The reactions that lead to these modifications are catalyzed by different enzymes such as methyltransferases, acetylases, kinases. These groups of enzymes are collectively referred to as the ‘writers.’
The reactions that catalyze the removal of these chemical groups are catalyzed by enzymes such as demethylases, deacetylases, and phosphatases. These enzymes are collectively referred to as the ‘erasers.’
Amongst the numerous possible combinations of different histone variants and amino-terminal end modifications, only certain coordinated sets are known to occur. Some of these combined sets of modifications encode a specific signal for the cell.
For example, one set of modifications signals DNA damage and the need for repair. Another signals gene expression, while others signal gene silencing or chromatin modification like the establishment and spread of heterochromatin.
This encoding system is referred to as the ‘Histone Code.’
The signals encoded in these modifications are decoded by specific regulatory proteins called ‘readers.’ These proteins and multiprotein complexes contain various small domains, each of which recognizes a particular histone mark.
They bind tightly to a region of chromatin that contains several different histone marks and attract additional protein complexes with catalytic activities. This leads to specific biological functions such as chromatin modifications, gene expression, and gene silencing.
View the full transcript and gain access to JoVE Core videos
Q1: What are the four core histone proteins found in a nucleosome?
The nucleosome core contains four histone proteins: H2A, H2B, H3, and H4. These core histones form the protein octamer around which DNA wraps. In addition to these standard histones, eukaryotes possess variants of each histone type, except H4, which provide functional diversity in chromatin regulation and gene expression.
Q2: How do histone modifications affect DNA-histone interactions?
Histone acetylation increases negative charge on histones, weakening DNA-histone interactions and loosening chromatin structure, allowing greater DNA access. Conversely, methylation increases positive charge, strengthening DNA-histone affinity and promoting chromatin compaction. These opposing effects make acetylation associated with gene activation and methylation with gene silencing.
Q3: What is the histone code and how does it function?
The histone code is a system where coordinated sets of histone modifications encode specific cellular signals. Different modification combinations signal DNA damage, gene expression, gene silencing, or chromatin modifications. Regulatory proteins called readers recognize these marks, bind to chromatin regions, and recruit additional protein complexes to execute specific biological functions.
Q4: What enzymes catalyze histone modifications and their removal?
Writer enzymes like methyltransferases, acetylases, and kinases catalyze histone modifications including acetylation, methylation, and phosphorylation. Eraser enzymes such as demethylases, deacetylases, and phosphatases remove these modifications. This dynamic system allows cells to rapidly alter chromatin states and regulate gene expression in response to developmental and environmental signals.
Q5: Where are histone modifications located on the nucleosome?
Histone modifications occur on the amino-terminal tails of core histones, which protrude from the nucleosome and comprise approximately 30 amino acids. These highly unstructured and mobile tails are subjected to covalent modifications including acetylation of lysines, phosphorylation of serines, and mono-, di-, or tri-methylation of lysines.
Q6: How are histone modifications inherited through cell division?
Histone modifications are epigenetically inherited, meaning they are not genetically coded but faithfully passed to daughter cells during cell division as epigenetic memory. This inheritance of chromatin structures allows cells to maintain gene expression patterns and chromatin states across generations without changes to DNA sequence.
Q7: What is the relationship between histone acetylation and gene expression?
Acetylated histones are associated with active gene expression, while hypoacetylated histones correlate with gene repression. For example, the beta-globin gene in erythroid cells is associated with acetylated histones that increase its expression, whereas in non-erythroid cells where the gene is inactive, it associates with nonacetylated histones.