HDAC inhibitors and a possible 'blood biomarker'

One way the Huntington’s disease gene causes damage is by interfering with the control of many other genes. HDACHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to inhibitors are drugs that aim to correct this, and researchers are working on bringing them to human trials. Meanwhile, the world of HDACsHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to has produced an interesting lead in the search for biomarkers to help us test drugs.

The recipe book

A gene is a recipe, spelled out in DNA, that tells our cells how to make a particular protein. Proteins are the molecular machines that do most of the hard work inside cells.

The HD gene is one of thousands that each of our cells carries. It’s a good example of how a small change in a gene can cause big changes in the body. In the case of HD, a small mistake in the gene – like a spelling mistake in a recipe – causes cells to produce the mutant huntingtin proteinhuntingtin protein The protein produced by the HD gene., which causes all the problems and symptoms of Huntington’s disease.

How genes are controlled

But there’s more to cooking than just following a single recipe. First, it’s important to choose which recipes in the book to follow, then you have to decide how much of each recipe to make. If you were holding a dinner party, it would be rather odd to cook twenty different soups and nothing else, or to prepare a meal for two people when you’re expecting a hundred guests.

It’s just as important that our cells choose the right gene recipes, and follow each recipe the correct number of times, to make sure that the right amount of each protein is made. It’s also important for cells to adapt because different situations call for different amounts of each protein.

The first step in reading a gene is to make a working copy from a DNA-like chemical called RNARNA the chemical, similar to DNA, that makes up the 'message' molecules that cells use as working copies of genes, when manufacturing proteins.. That’s called transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA.. Controlling the activation levels of different genes is called transcriptional regulationtranscriptional regulation the mechanisms that control the activation levels of different genes. When it goes wrong, that’s called transcriptional dysregulation.

Transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA. factors and histoneshistone special proteins that our DNA wraps around to stabilize and protect it

Cells have complex machinery for controlling gene activation levels that allow them to react to different situations. Proteins called transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA. factors are important. When the time is right, they attach to specific places in our DNA, like you might put a bookmark in a recipe book. The cell then spots the bookmark and starts reading the gene. Other transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA. factors tell cells not to read a particular gene, while some control many related genes all at once.

If you had a book of secret recipes, you’d want to keep it well protected, perhaps by padlocking it shut or locking it away. Cells are just as protective, and wrap their DNA round proteins called histoneshistone special proteins that our DNA wraps around to stabilize and protect it. Before a gene can be read, first the DNA has to be unwrapped from the histoneshistone special proteins that our DNA wraps around to stabilize and protect it.

Gene regulation problems in HD

Now imagine if you were cooking a meal from a recipe, but someone who was supposed to be helping you, kept you telling you to make twice as much as you need, or moving your bookmarks around so that you follow the wrong recipe. Chances are, that would end in a big mess.

In a way, that’s what happens in Huntington’s disease.

The mutant huntingtin proteinhuntingtin protein The protein produced by the HD gene. behaves a lot like that unhelpful assistant. We know that one of the main ways in which mutant huntingtin causes damage is by messing up the activation levels of other genes.

Partly, mutant huntingtin causes problems directly, by binding to the DNA like a transcription factortranscription factor a gene-control protein. In response to signals from inside and outside cells, transcription factors attach to the DNA and cause specific genes to be more or less activated, producing more or less of the corresponding protein.. And partly, it does it indirectly, by messing with other transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA. factors.

The end result has been shown many times in Huntington’s disease – widespread chaos in the control of gene activation. And since each gene is important in its own way, you can see how these effects of the mutant protein could be very widespread and damaging to cells.

HDACsHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to, exposing the DNA

As we’ve seen, histoneshistone special proteins that our DNA wraps around to stabilize and protect it are important in controlling what bits of our DNA are protected and what bits are exposed.

Histoneshistone special proteins that our DNA wraps around to stabilize and protect it themselves are controlled by a chemical switching process. A tag called ‘acetylacetyl a chemical tag that can be added to proteins or removed from them’ is attached to the histonehistone special proteins that our DNA wraps around to stabilize and protect it or removed from it.

When a histonehistone special proteins that our DNA wraps around to stabilize and protect it has an acetylacetyl a chemical tag that can be added to proteins or removed from them attached to it, it keeps the DNA protected. When the acetylacetyl a chemical tag that can be added to proteins or removed from them is removed, the DNA is more exposed.

The protein machines that remove the acetylacetyl a chemical tag that can be added to proteins or removed from them tags are called – brace yourself – histone de-acetylaseHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to enzymes. For obvious reasons they’re usually referred to as HDACsHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to – pronounced “H-dacks”.

Because HDACsHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to remove acetylacetyl a chemical tag that can be added to proteins or removed from them from histoneshistone special proteins that our DNA wraps around to stabilize and protect it, their overall effect is to leave stretches of DNA exposed and potentially vulnerable to the chaos caused by the mutant huntingtin proteinhuntingtin protein The protein produced by the HD gene..

HDACHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to inhibitors: protecting the DNA

Scientists working on treatments for Huntington’s disease have wondered whether it might be possible to prevent or reverse some of the gene activation chaos caused by the mutant huntingtin proteinhuntingtin protein The protein produced by the HD gene..

HDACsHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to are particularly interesting, because a drug that reduced the activity of HDACsHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to ought to protect the DNA against some of the chaos. Drugs that do this are called HDACHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to inhibitors.

Gene regulation problems contribute to the development of some cancers, and in fact two HDACHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to inhibitors are already approved for the treatment of certain blood cancers, with many more being studied.

HDACHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to inhibitors in HD mice

Many HD researchers see HDACHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to inhibitors as among the most likely to lead to successful treatments for patients.

Building on the work of others in yeast and fruit flies, in 2006 researchers led by Prof Gill Bates, of King’s College London, published a landmark study of an HDACHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to inhibitor called SAHASAHA an HDAC-inhibitor drug. Its full name is Suberoylanilide hydroxamic acid.. HD mice given SAHASAHA an HDAC-inhibitor drug. Its full name is Suberoylanilide hydroxamic acid. in their food performed much better than usual on tests of movement.

However, the SAHASAHA an HDAC-inhibitor drug. Its full name is Suberoylanilide hydroxamic acid.-treated mice lost more weight than expected – warning of toxic side effects if the drug were used in humans.

Harmful drug side effects might not be a deal-breaker in conditions like cancer, where treatment is usually in short bursts. But in HD they’d be a major concern, because ultimately we’d like to treat people with the expanded HD gene before they have any symptoms – and treatment may go on for years or decades.

Improving the drugs

There are many different histonehistone special proteins that our DNA wraps around to stabilize and protect it proteins, and many different HDACHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to enzymes that behave differently and protect or expose different bits of DNA in different circumstances. SAHASAHA an HDAC-inhibitor drug. Its full name is Suberoylanilide hydroxamic acid. is a general inhibitor across the range of HDACHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to enzymes.

But subsequent work by Bates’ team, and others, has revealed one HDACHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to in particular – HDACHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to-4 – to be particularly interesting. Disabling HDACHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to-4 genetically produced the benefits of SAHASAHA an HDAC-inhibitor drug. Its full name is Suberoylanilide hydroxamic acid. treatment, without the weight loss.

A major effort is now underway to develop and test drugs that will inhibit HDACHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to-4 safely and without interfering with the other HDACHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to enzymes. It’s hoped that this will lead to drugs to slow progression in HD while minimizing the risk of harmful effects.

So what’s new in HDACsHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to?

As well as requests for an HDACHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to article from HDBuzz readers, our attention was drawn to HDACsHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to and HDACHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to inhibitors by a recent paper in the journal PNAS by Dr Clemens Scherzer of Harvard Medical School, Massachusetts.

Scherzer’s group began looking for biomarkers of Huntington’s disease. A biomarkerbiomarker a test of any kind – including blood tests, thinking tests and brain scans – that can measure or predict the progression of a disease like HD. Biomarkers may make clinical trials of new drugs quicker and more reliable. is a test that can be used to measure or predict progression of a disease. We need good biomarkers so that we can test drugs more quickly.

Scherzer used some nifty technology called expression profilingexpression profiling a technique that allows measurement of the activation levels of many thousands of genes at once to look at all the different RNARNA the chemical, similar to DNA, that makes up the 'message' molecules that cells use as working copies of genes, when manufacturing proteins. message molecules in the blood of HD patients. The amount of each RNARNA the chemical, similar to DNA, that makes up the 'message' molecules that cells use as working copies of genes, when manufacturing proteins. is a measure of how activated a particular gene is. One of the most common RNARNA the chemical, similar to DNA, that makes up the 'message' molecules that cells use as working copies of genes, when manufacturing proteins. types corresponded to a gene called H2AFY, which is the recipe for a histonehistone special proteins that our DNA wraps around to stabilize and protect it protein called macroH2A1.

This was a big surprise, because if cells in HD patients are producing too many histoneshistone special proteins that our DNA wraps around to stabilize and protect it, it could really mess around with the control of gene activation.

Scherzer’s team checked the result in several different ways, in blood and brain from humans and several mice, and every time they looked, they found evidence of more of the gene or more of the histonehistone special proteins that our DNA wraps around to stabilize and protect it protein than expected.

When HD mice were given the HDACHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to-inhibiting drug phenylbutyratephenylbutyrate a 'non-selective' HDAC inhibitor that affects all HDACs without targeting any particular HDAC enzyme, levels of the histonehistone special proteins that our DNA wraps around to stabilize and protect it protein fell. And when measured in blood samples from a clinical trialclinical trial Very carefully planned experiments designed to answer specific questions about how a drug affects human beings of phenylbutyratephenylbutyrate a 'non-selective' HDAC inhibitor that affects all HDACs without targeting any particular HDAC enzyme in HD patients that was performed several years ago, levels of the H2AFY message were lower when patients had been taking the drug.

So is H2AFY a biomarkerbiomarker a test of any kind – including blood tests, thinking tests and brain scans – that can measure or predict the progression of a disease like HD. Biomarkers may make clinical trials of new drugs quicker and more reliable.?

Some news sources have reported that the H2AFY message molecule is a biomarkerbiomarker a test of any kind – including blood tests, thinking tests and brain scans – that can measure or predict the progression of a disease like HD. Biomarkers may make clinical trials of new drugs quicker and more reliable. for HD – a blood test that will enable us to run clinical trials in HD.

Unfortunately it’s not quite that simple – as Scherzer’s team themselves point out in their paper. Finding biomarkers is almost as difficult as finding treatments, and each possible biomarkerbiomarker a test of any kind – including blood tests, thinking tests and brain scans – that can measure or predict the progression of a disease like HD. Biomarkers may make clinical trials of new drugs quicker and more reliable. needs to be tested in many different ways. The most important test of a biomarkerbiomarker a test of any kind – including blood tests, thinking tests and brain scans – that can measure or predict the progression of a disease like HD. Biomarkers may make clinical trials of new drugs quicker and more reliable. is whether it can predict whether a drug will work. Since no drug has worked yet, that’s a bit of a catch-22. It means we have to design studies carefully, to develop and test our drugs and biomarkers at the same time.

For a test to be a useful biomarkerbiomarker a test of any kind – including blood tests, thinking tests and brain scans – that can measure or predict the progression of a disease like HD. Biomarkers may make clinical trials of new drugs quicker and more reliable., we need to understand exactly what it means. Right now, we have very little idea why there’s more than expected of the H2AFY gene message, and the histonehistone special proteins that our DNA wraps around to stabilize and protect it protein the gene is a recipe for. We have even less understanding of how these changes link up with what we know already about how HD causes damage.

Onward!

This is the kind of stuff that scientists love to get their teeth into. Gene activation chaos – a major way in which the Huntington’s disease mutation causes damage. Histoneshistone special proteins that our DNA wraps around to stabilize and protect it shielding the DNA, HDACHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to enzymes exposing it and HDACHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to inhibitors hiding it again. The challenge of developing HDACHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to-4 inhibitors that are safe. And now a new mystery – the H2AFY gene message, linked to both histoneshistone special proteins that our DNA wraps around to stabilize and protect it and HDACHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to inhibitors, which might help us find useful biomarkers.

With many research teams around the world tackling the issue from different angles, you certainly haven’t heard the last of HDACHDAC histone de-acetylases (HDACs) are machines that remove acetyl tags from histones, causing them to release the DNA they're attached to inhibition.

Learn more

• Article reporting success of SAHA treatment in HD mice by Prof Bates’ group in PNAS (full article requires payment or subscription)
• Article on H2AFY and macroH2A1 by Dr Scherzer’s group in PNAS (full article requires payment or subscription)