Chromatin remodeling is one of the most important processes in mammalian development. It plays a crucial role in gene expression and cell differentiation. The mechanism of chromatin remodeling is complex and involves many different types of proteins. These proteins interact with each other, with DNA and with histones. They form complexes called heterochromatin. Histone marks are usually located at specific sites within the genome (called loci). These changes in the DNA influence how accessible a particular region of DNA is. In other words, by labeling specific regions as either accessible or inaccessible, the cell influences which genes are expressed and which ones aren’t.
The three mechanisms of chromatin remodeling include:
1. ATP-dependent remodeling – this is the most common.
ATP (adenosine triphosphate) is a nucleotide made up of adenine, ribose and phosphates. It acts as a ‘molecular unit of currency’ for energy transfer within cells.
ATP-dependent remodeling uses the energy obtained from ATP to change the shape or position of a protein. The energy is stored within the phosphate bonds of ATP, and when these bonds break, the resulting energy releases as heat.
2. CTCF-mediated – CTCF (CCCTC-binding factor) is a protein that binds to itself and to DNA.
It can bind to two separate locations on DNA and can connect these two regions. In this case, the term “connect” means that these two regions become more accessible to each other, and also become disconnected from the rest of the chromatin.
This action is called ‘condensation’.
3. Cohesin-mediated – cohesin is a multiprotein complex that holds sister chromatids together until mitosis.
During the initiation of mitosis, the cohesin complex is cleaved by separase. This complex is a large ring-shaped protein composed of several subunits.
It can be found in the cytoplasm and also attach to chromosomes. The complex holds the two arms of a duplicated chromosome together until they are ready to be separated during division.
These three mechanisms are not mutually exclusive. Different combinations of proteins are involved in these three types of remodeling.
Besides these types, there is another remodeling mechanism that does not involve the remodeling of nucleosomes. This type of mechanism is called ‘histone code’; the addition or removal of modifications to histones.
Remodeling components and structures
In eukaryotes, the remodeling machinery has several components. These are:
There are several types of remodeling complexes. Some of these include the following:
Types of reorganization
The main types of reorganization include:
These types can be used in various combinations. For example, in the case of ‘disruption and re-establishing’, the complex can bind to the DNA but not change its shape.
It will then be moved away from the region by other factors.
There are several ways in which these types are organized and classified. One way is by ‘directionality’.
Is the remodeling process directed towards DNA or away from it?
In some cases, it seems that the process can be both, depending on which factors are involved. The other way is by ‘function’. In this case, the factors involved in the reorganization may carry out several different functions.
Another way is by ‘subunit organization’. This refers to the fact that the remodeling complexes contain several different subunits.
These subunits may perform similar or different functions.
In some cases, the same factor can be involved in several different processes. For example, the protein Smarca5 is involved in both activation and repression; it is present in several remodeling complexes that either activate or repress genes.
Chromatin remodeling is a very complex process, and many of the steps involved are not yet fully understood. The first step in remodeling is the action of ATP-dependent chromatin remodeling enzymes.
This action is ATP-dependent; it uses the energy of ATP to change the shape of DNA.
Many types of remodeling enzymes exist, each with a different method of action. These include the following:
The most common action of these enzymes is the formation and breaking of hydrogen bonds. This process changes the nucleosome structure and allows other mechanisms to act on the DNA.
These enzymes help move DNA, and may also change its shape. These are the most common enzymes involved in remodeling.
They help integrate the newly synthesized DNA into the chromosome, allowing it to be copied and passed on during cell division.
These enzymes act by cutting the DNA, then joining the two free ends together. This is the method often used in gene activation.
There are several types of these enzymes, which act on different parts of the DNA:
These enzymes are involved in the removal of methyl groups from DNA. This process is involved in both gene activation and repression.
The most important part of the action of these enzymes is not known; it may be the direct action of the enzyme, or the interaction with other proteins. These are some of the newest types of enzymes to be discovered, and their exact actions are not yet known.
These are enzymes that may act to strengthen the bonds between two nucleotides.
These are very rare enzymes, which act to break the phosphodiester bond. This is the bond that holds the two free ends of DNA together when it has been cut by a nuclease enzyme.
This can either be done to activate or repress a gene.
These are enzymes that cut the DNA; this process is not yet fully understood, but it may be involved in switching off genes. There are several types of these enzymes, which act on different parts of the DNA:
The active sites of these enzymes are known to be in a deep hydrophobic pocket. This pocket binds to a single stranded flap of DNA, which is then cut by an enzyme.
These enzymes are involved in activating genes.
These are the most recently discovered type of endonuclease. Unlike the other types of nuclease, they cut the DNA in the middle of the nucleotide pairs, instead of at the phosphodiester bond.
This produces a single stranded flap that then folds back and binds to the active site of the enzyme, which then cuts both strands at the phosphodiester bond. This process is very similar to the bacterial RecF pathway for repairing damaged DNA.
These are very rare enzymes, which bind to the DNA and cause a break in the phosphodiester bond. The break is then sealed, either by another modifying enzyme or by the binding of ATP.
The process is then repeated, and as a result the DNA is sheared. This process may be involved in the activation of genes.
The active site of these enzymes is known to be a beta sheet. As the name suggests, it causes the DNA to fragment into sections of base pairs.
This process is involved in gene activation.
These are enzymes that cause the DNA to fragment into sections of base pairs. This process is involved in gene activation and repression.
These are enzymes that cut the DNA, but don’t go all the way through it. This process causes a single strand of the DNA to fold back on itself, and for the enzyme to bind to this.
It then cuts both strands at the phosphodiester bond to cause a double stranded break in the DNA. The single strand is then released, and another enzyme may bind to the newly exposed phosphates and add a new nucleotide. This process is involved in activating genes.
These are very rare enzymes. They cause a single stranded flap to be formed at one end of the cut in the DNA.
This is then bound to the active site of the enzyme; the other end of the flap is then bound to an unbroken segment of DNA, and the enzyme causes a DNA ligase to seal the strand.
Sources & references used in this article:
- Histone acetylation and chromatin remodeling (PD Gregory, K Wagner, W Hörz – Experimental cell research, 2001 – Elsevier)
- EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma (N Riggi, B Knoechel, SM Gillespie, E Rheinbay… – Cancer cell, 2014 – Elsevier)
- IFN-γ abrogates endotoxin tolerance by facilitating Toll-like receptor-induced chromatin remodeling (J Chen, LB Ivashkiv – … of the National Academy of Sciences, 2010 – National Acad Sciences)
- Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum (A Kumar, KH Choi, W Renthal, NM Tsankova… – Neuron, 2005 – Elsevier)
- ATP-dependent chromatin-remodeling complexes (M Vignali, AH Hassan, KE Neely… – Molecular and cellular …, 2000 – Am Soc Microbiol)
- Unique chromatin remodeling and transcriptional regulation in spermatogenesis (P Sassone-Corsi – Science, 2002 – science.sciencemag.org)