I have been reading up on the issues around acetylation of the histone and I have some ideas as to the interplay between acetylation and deacetylation.
There are two steps in creating proteins. The first is called "transcription". This is where a complex called RNA Polymerase II (RNA Pol II or RNAPII) travels down the gene creating messenger RNA (mRNA) as essentially a local copy. The second is "translation" where proteins get created from the mRNA. Although I think there are important metabolic constraints on protein creation in this post I am going to concentrate on "transcription".
One of the key things about Transcription is that for RNA Pol II to get at the genes to copy from them the genes need to be opened up. The opening up process is where an acetyl group (think vinegar without the hydrogen ion or oxygen which would attract the hydrogen) is added to the histone which holds the DNA. This causes it to open up as a result of the electric charge being negative.
Once RNA Pol II has copied the gene a process called deacetylation occurs where the acetyl group is removed and the gene goes back into a state where it is less accessible. This is good for protecting the gene from damage by other chemicals.
What is very clear is that when there is a shortage of the molecules needed for acetylation that RNA Pol II stops. Part of the RNA Pol II complex is the histone acetyl transferase and obviously if it needs a chemical to do its job of acetylation then it would have to wait for it.
What is not clear is what the interplay between deacetylation and RNA Pol II is. Deacetylation is done by HDACs (Histone deacetylases).
Having read quite a few papers about this I think what happens is this. Although acetylation is done as part of the RNA Pol II complex, deacetylation is a bit more random. Deacetylation depends upon the availability of HDACs and can happen at any time. It requires the HDAC and also some NAD+ (for Class III).
Hence I think Deactylation can start after the gene has been fully transcribed, but it can also happen when RNA Pol II is in the process of transcribing the gene. The big question is what happens if the HDAC deactylates the histone where RNA Pol II is stalled.
RNA Pol II at times moves backwards (not far) and forwards. However, I think what happens is that if it conflicts with the HDAC then under some circumstances RNA Pol II is terminated. If not enough of the gene has been transcribed then the protein is not produced.
The process of deacetlation depends upon both the number of HDACs around, but also whether or not they are inhibited. If they are inhibited then there is a greater chance that RNA Pol II will finish its task before being terminated by an HDAC. An interesting point about this, however, is that if the HDAC is inhibited then the cell will produce more of that HDAC (but not enough to remove the effect of the inhibition.
So we see from that HDAC inhibitors are likely to ensure that longer genes continue to function. A very strong inhibition can cause a shortage of ATP in the cell and cell death so we do need to be careful not to go too far.
There are a number of situations where is can be seen that this process is working. An obvious one is the Queen Bee where one key component of Royal Jelly (which creates the phenotype of the Queen Bee) is an HDAC inhibitor. The other one is molecules like Resveratrol (which I don't like because it is a cox-1 inhibitor, but I will leave that for another time).
These molecules will inhibit HDAC so longer genes are more likely to be transcribed, but at the same time you would expect the body to produce more of the HDACs. Sirtuins are class III HDACs - likely to be affected the same way. Having read Charles Brenner's comments on this I agree with him that they are not longevity genes, but their role in prematurely terminating RNA Pol II (hypothetically) makes it clear that they are important for metabolism, but more is not better.
Note: I am not quite sure of the situation with Resveratrol which is reported to be an inhibitor of classes I, II and IV of HDAC, but I cannot find whether it actually inhibits class III. If anyone has better information on this could they please give me references so I can make sure what is in the last paragraph is correct. I do, however, think the principles are correct in that directly inhibiting an enzyme is likely to result in greater expression of the mRNA. Furthermore I am not clear as to which HDAC's are more active. It strikes me that the nature of class III and the fact that they uniquely rely on NAD+ rather than being part of a complex may mean that they do more of the deacetylation - or at least are the backup system which applies when the others don't. However, I don't know how much is known about this.
There are two steps in creating proteins. The first is called "transcription". This is where a complex called RNA Polymerase II (RNA Pol II or RNAPII) travels down the gene creating messenger RNA (mRNA) as essentially a local copy. The second is "translation" where proteins get created from the mRNA. Although I think there are important metabolic constraints on protein creation in this post I am going to concentrate on "transcription".
One of the key things about Transcription is that for RNA Pol II to get at the genes to copy from them the genes need to be opened up. The opening up process is where an acetyl group (think vinegar without the hydrogen ion or oxygen which would attract the hydrogen) is added to the histone which holds the DNA. This causes it to open up as a result of the electric charge being negative.
Once RNA Pol II has copied the gene a process called deacetylation occurs where the acetyl group is removed and the gene goes back into a state where it is less accessible. This is good for protecting the gene from damage by other chemicals.
What is very clear is that when there is a shortage of the molecules needed for acetylation that RNA Pol II stops. Part of the RNA Pol II complex is the histone acetyl transferase and obviously if it needs a chemical to do its job of acetylation then it would have to wait for it.
What is not clear is what the interplay between deacetylation and RNA Pol II is. Deacetylation is done by HDACs (Histone deacetylases).
Having read quite a few papers about this I think what happens is this. Although acetylation is done as part of the RNA Pol II complex, deacetylation is a bit more random. Deacetylation depends upon the availability of HDACs and can happen at any time. It requires the HDAC and also some NAD+ (for Class III).
Hence I think Deactylation can start after the gene has been fully transcribed, but it can also happen when RNA Pol II is in the process of transcribing the gene. The big question is what happens if the HDAC deactylates the histone where RNA Pol II is stalled.
RNA Pol II at times moves backwards (not far) and forwards. However, I think what happens is that if it conflicts with the HDAC then under some circumstances RNA Pol II is terminated. If not enough of the gene has been transcribed then the protein is not produced.
The process of deacetlation depends upon both the number of HDACs around, but also whether or not they are inhibited. If they are inhibited then there is a greater chance that RNA Pol II will finish its task before being terminated by an HDAC. An interesting point about this, however, is that if the HDAC is inhibited then the cell will produce more of that HDAC (but not enough to remove the effect of the inhibition.
So we see from that HDAC inhibitors are likely to ensure that longer genes continue to function. A very strong inhibition can cause a shortage of ATP in the cell and cell death so we do need to be careful not to go too far.
There are a number of situations where is can be seen that this process is working. An obvious one is the Queen Bee where one key component of Royal Jelly (which creates the phenotype of the Queen Bee) is an HDAC inhibitor. The other one is molecules like Resveratrol (which I don't like because it is a cox-1 inhibitor, but I will leave that for another time).
These molecules will inhibit HDAC so longer genes are more likely to be transcribed, but at the same time you would expect the body to produce more of the HDACs. Sirtuins are class III HDACs - likely to be affected the same way. Having read Charles Brenner's comments on this I agree with him that they are not longevity genes, but their role in prematurely terminating RNA Pol II (hypothetically) makes it clear that they are important for metabolism, but more is not better.
Note: I am not quite sure of the situation with Resveratrol which is reported to be an inhibitor of classes I, II and IV of HDAC, but I cannot find whether it actually inhibits class III. If anyone has better information on this could they please give me references so I can make sure what is in the last paragraph is correct. I do, however, think the principles are correct in that directly inhibiting an enzyme is likely to result in greater expression of the mRNA. Furthermore I am not clear as to which HDAC's are more active. It strikes me that the nature of class III and the fact that they uniquely rely on NAD+ rather than being part of a complex may mean that they do more of the deacetylation - or at least are the backup system which applies when the others don't. However, I don't know how much is known about this.
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