Friday, April 2, 2010

Chromatin Chapter 2: Modifications and the Histone Code

As mentioned, histones can be modified as well (this was mentioned briefly in the DNA repair posts).  Poly(ADP)-ribosylation causes the histones to bind less tightly to the DNA via repulsive negative charges.  This modification can be found at sites of DNA under repair.  Ubiquitination of H2A and H2B marks the proteins for degradation.  Phosphorylation tends to compact chromatin, but the mechanism by which this is done is unknown.  Finally, acetylation via HATs (histone acetyl transferases) on lysine and arginine residues in the core histones neutralizes the positive charge of the histones and causes them to repel from the DNA, leading to enhanced transcriptional activity. 

Poly(ADP) Ribosylation
Histones repel DNA, opening it for DNA repair
Degradation of H2A and H2B
Chromatin compaction
Histones repel DNA, opening it for transcription and DNA repair

Naively, one would consider the most important aspect of gene regulation to be the primary DNA sequence.  Nonetheless, chromatin plays a part in both transcription and replication, and the importance of this regulation is becoming more and more apparent.  One of the primary mechanisms by which replication and transcription are regulated via chromatin is from acetylation of histones.  Acetylation is performed by histone acetyl transferases (HATs), of which there are two kinds: A-HATs that mediate transcription-related acetylation, and B-HATs that modulate replication-related acetylation.  The most frequently observed acetylation events occur on histones H3 and H4, with A-HAT acetylating lysines 8 and 16 of H4 and 14 of H3; B-HAT acetylates lysines 5 and 12 of H4 and 9 of H3.

During DNA replication (when B-HATs are most active); histone acetylation is linked to chromatin maturation of the nascent DNA strand.  p48 is a histone escort that is in complex with a B-HAT, (Hat1p).  Chromatin assembly factor (CAF1) displaces B-HAT to form the chromatin assembly complex.  Histone de-acetylase (HD1) displaces CAF1 in the complex and removes acetylation events to mature the chromatin.  Acetylation events that remain on histones are recognized by specific proteins with specific domains, called bromodomains, that recognize and bind the acetylated lysine residues.

In contrast to histone acetylation, methylation via histone methyl transferases (such as human SUV39H1) mediates gene repression.  Gene activity is modulated by the balance of methylation and acetylation.  As mentioned, there are proteins that bind acetylated histones via bromodomains; similarly, there are proteins with chromodomains that bind methylated histones.  Two such proteins are Swi6 and HP1 (heterochromatin protein 1). 

It is important to note that actively transcribed genes are complexed with nucleosomes.  However, the chromatin in the region of these active genes tend to have acetylated histones and are also tend to be missing a couple nucleosomes from the promoter region.  Histone H1, the linker histone, is also missing from regions of the gene, and little DNA methylation is detected.  The DNA at actively transcribed genes is also more susceptible to nuclease attack and digestion.   

The Histone Code
Data considering differential gene regulation based on histone methylation and acetylation lead to the development of the histone code hypothesis.  The histone code is considered the pattern of markings on histones that cover the DNA.  Specific markings of these histones indicate newly-replicated chromatin, damaged DNA, and transcriptionally active or repressed regions.  Reader complexes recognize the marks on the chromatin and perform a function, while writer complexes such as HATs and methyltransferases mark the nucleosomes.  Write-read cycles spread chromatinization along DNA by consisting of DNA reader/writer complexes that bind a modified histone and create a marking on a nearby histone that then propagates chromatin modifications.  Barrier DNA sequences block these reader-writer complexes from expanding beyond a set boundary.   

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