A back-to-front hidden message in the HD gene?

The double-helix of our DNA contains a backup copy of every gene. Sometimes the backup DNA produces hidden ‘messages’ that can alter things in our cells. Researchers have now discovered a message in the backup copy of the Huntington’s disease gene, which appears to be able to influence how much huntingtin proteinhuntingtin protein The protein produced by the HD gene. is made.

Unzip your genes!

You might have heard of the phrase ‘double-helix’, used to describe the DNA that our genes are made from. But what exactly does that mean?

Well, each gene is a set of instructions for how to make a protein. The instructions are ‘written’ in a sequence of ‘letters’ which we call bases. Each base is a small chemical, and the bases are joined together in long strands. The bases are abbreviated as A, C, G and T.

A single strand doesn’t sound much like a double-helix – and that’s because the DNA that contains the instructions for making proteins is only half the story. The bases in our DNA naturally like to pair up like dance partners – A pairs with T, and C pairs with G.

It’s this pairing that gives DNA its double-helix structure. Each base on the ‘business’ strand lines up with a partner, and the partners all join up to form another strand. The two strands wrap around like a spiral staircase – finally, the double-helix. The scientific name for the business strand is the sense strand; the other one is called the anti-senseanti-sense the half of the DNA double-helix that is mostly used as a backup, but sometimes produces message molecules strand.

Our DNA is arranged like this for two reasons.

Firstly, it makes copying the DNA easier, when cells want to divide: all the cell has to do is unzip the DNA down the middle so that the strands separate, then throw bases at the two strands. The bases stick to their partners, leaving two exact copies of the original double-helix!

The second reason is that if the DNA gets damaged, the ‘spare’ anti-sense strandanti-sense the half of the DNA double-helix that is mostly used as a backup, but sometimes produces message molecules can be used as a backup copy to tell the cell’s DNA repair equipment how to fix the sense DNA.

Anti-senseanti-sense the half of the DNA double-helix that is mostly used as a backup, but sometimes produces message molecules messages

The anti-sense strandanti-sense the half of the DNA double-helix that is mostly used as a backup, but sometimes produces message molecules clearly has its uses. But until recently it was thought that all the important work of the DNA was done by the sense strandsense strand the half of the DNA double-helix that contains instructions for most proteins. The 'business' strand.. That all changed a few years ago when scientists realized that some genes have useful DNA hidden in their anti-senseanti-sense the half of the DNA double-helix that is mostly used as a backup, but sometimes produces message molecules strands.

That’s possible because the two strands of our DNA are chemically very similar. The main difference is that the machinery that reads the DNA can only run in one direction along each strand, like cars traveling in opposite directions along the two lanes of a road. The sense and anti-senseanti-sense the half of the DNA double-helix that is mostly used as a backup, but sometimes produces message molecules strands are read in different directions.

What do we mean by ‘useful DNA’? Well, when a cell reads a gene, the first thing that’s produced is a single-stranded copy of the gene. This copy of the gene is made with chemicals called RNARNA the chemical, similar to DNA, that makes up the 'message' molecules that cells use as working copies of genes, when manufacturing proteins., which are very similar to those in the original DNA. The RNARNA the chemical, similar to DNA, that makes up the 'message' molecules that cells use as working copies of genes, when manufacturing proteins. copy is used by the protein-building machinery of the cell. Using these copies of genes, rather than constantly using the original gene, means the all-important DNA is protected from constant use.

Historically, scientists thought that the RNARNA the chemical, similar to DNA, that makes up the 'message' molecules that cells use as working copies of genes, when manufacturing proteins. in cells was mostly these copies of genes, or ‘messages’ as they called them. But in the last few years we’ve learned that cells are full of RNARNA the chemical, similar to DNA, that makes up the 'message' molecules that cells use as working copies of genes, when manufacturing proteins. of all different types – not just copies of genes that are going to be made into proteins, but a baffling range of RNARNA the chemical, similar to DNA, that makes up the 'message' molecules that cells use as working copies of genes, when manufacturing proteins. in different sizes and patterns, with functions that we don’t fully understand. Some of these RNAs in the cell were actually made from the anti-senseanti-sense the half of the DNA double-helix that is mostly used as a backup, but sometimes produces message molecules, rather than the sense strandsense strand the half of the DNA double-helix that contains instructions for most proteins. The 'business' strand.. In some genetic diseases, an anti-senseanti-sense the half of the DNA double-helix that is mostly used as a backup, but sometimes produces message molecules message molecule is a cause of damage.

An anti-senseanti-sense the half of the DNA double-helix that is mostly used as a backup, but sometimes produces message molecules message in the HD gene

“A few years ago scientists realized that some genes have useful DNA hidden in their anti-sense strands.”

Prof Russell Margolis is a Huntington’s disease researcher at Johns Hopkins University, with an interest in anti-senseanti-sense the half of the DNA double-helix that is mostly used as a backup, but sometimes produces message molecules messages, so he decided to look at the anti-sense strandanti-sense the half of the DNA double-helix that is mostly used as a backup, but sometimes produces message molecules of the gene that causes HD. The gene, called HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15, is a recipe for the huntingtin proteinhuntingtin protein The protein produced by the HD gene.. In people with HD, or who are going to get it, a stretch at the beginning of the gene has more than the usual number of repeats of the sequence CAG.

Figuring out the anti-senseanti-sense the half of the DNA double-helix that is mostly used as a backup, but sometimes produces message molecules sequence for the HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 gene is pretty easy, because we already know the sequence of the sense strandsense strand the half of the DNA double-helix that contains instructions for most proteins. The 'business' strand., and we know that the bases of DNA only partner together in specific ways. For example, where the sense strandsense strand the half of the DNA double-helix that contains instructions for most proteins. The 'business' strand. reads C-A-G-C-A-G-C-A-G and so on, reading backwards and switching to the opposite partnered bases, the anti-sense strandanti-sense the half of the DNA double-helix that is mostly used as a backup, but sometimes produces message molecules must read C-T-G-C-T-G-C-T-G.

Using brain tissue donated by Huntington’s disease patients, Margolis looked at whether an anti-senseanti-sense the half of the DNA double-helix that is mostly used as a backup, but sometimes produces message molecules message from the HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 gene was present. He found that it was – and he also found it in brains donated by people without HD.

Margolis called the anti-senseanti-sense the half of the DNA double-helix that is mostly used as a backup, but sometimes produces message molecules HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 message HTTASHTTAS the anti-sense (backwards) version of the HTT gene – short for huntingtin anti-senseanti-sense the half of the DNA double-helix that is mostly used as a backup, but sometimes produces message molecules.

Consulting computer databases of all known proteins, Margolis found that HTTASHTTAS the anti-sense (backwards) version of the HTT gene wasn’t a recipe for any known protein. Though we can’t be sure, that probably means that the HTTASHTTAS the anti-sense (backwards) version of the HTT gene message is in cells, but doesn’t get as far as causing the cell to make a protein. But as we now know, sometimes anti-senseanti-sense the half of the DNA double-helix that is mostly used as a backup, but sometimes produces message molecules messages can do stuff on their own. So Margolis set out to find out what, if anything, the HTTASHTTAS the anti-sense (backwards) version of the HTT gene message molecule does in cells.

What does the message do?

Surprisingly, although the HTTASHTTAS the anti-sense (backwards) version of the HTT gene message was found in all the brains, the levels were lower in the HD brains, suggesting that something about HD brains reduces the amount of HTTASHTTAS the anti-sense (backwards) version of the HTT gene message. And the longer the CAG repeatCAG repeat The stretch of DNA at the beginning of the HD gene, which contains the sequence CAG repeated many times, and is abnormally long in people who will develop HD length, the less anti-senseanti-sense the half of the DNA double-helix that is mostly used as a backup, but sometimes produces message molecules message there was.

What about the other way round? Can the anti-senseanti-sense the half of the DNA double-helix that is mostly used as a backup, but sometimes produces message molecules message molecule influence the forwards-reading HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 gene? Looks like it can. Working in cells in the lab, Margolis’ team used a chemical switch to prevent the cells from producing the HTTASHTTAS the anti-sense (backwards) version of the HTT gene message. Those cells produced more of the forwards-reading huntingtin message.

That all seemed to make sense – in cells with an expanded CAG repeatCAG repeat The stretch of DNA at the beginning of the HD gene, which contains the sequence CAG repeated many times, and is abnormally long in people who will develop HD, there’s less HTTASHTTAS the anti-sense (backwards) version of the HTT gene (the anti-senseanti-sense the half of the DNA double-helix that is mostly used as a backup, but sometimes produces message molecules message). Because HTTASHTTAS the anti-sense (backwards) version of the HTT gene has the effect of lowering the levels of HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15, reducing HTTASHTTAS the anti-sense (backwards) version of the HTT gene increases levels of HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15.

A spanner in the works

That explanation works in itself, but if it’s true we’d expect the brains of people with HD to have more of the HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 message overall. But that’s not what we see – all brains have about the same amount of HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 message, regardless of whether their owner had HD.

Clearly – as is often the case – something different is happening in patient brains from what was seen in the lab.

Through more experiments looking at cells with different CAG repeatCAG repeat The stretch of DNA at the beginning of the HD gene, which contains the sequence CAG repeated many times, and is abnormally long in people who will develop HD lengths, Margolis was able to show that, as well as an effect of HTTASHTTAS the anti-sense (backwards) version of the HTT gene on HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 levels, the HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 gene also has effects on itself – and those effects were the exact opposite from the effects of HTTASHTTAS the anti-sense (backwards) version of the HTT gene.

So in someone with an expanded CAG in the HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 gene, there’s less of the HTTASHTTAS the anti-sense (backwards) version of the HTT gene message, so levels of the HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 message increase. But at the same time, the expanded HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 gene acts to decrease levels of its own message.

Overall the two effects cancel each other out, and HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 message levels end up the same!

Could the anti-senseanti-sense the half of the DNA double-helix that is mostly used as a backup, but sometimes produces message molecules message be useful anyway?

That sounds like a complicated way to get back to where we started. So have these discoveries told us anything that might be useful?

Although the two effects Margolis has shown cancel each other out normally, it’s still theoretically possible that they could be manipulated separately, to produce benefits.

Since the HTTASHTTAS the anti-sense (backwards) version of the HTT gene message lowers levels of HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 message, increasing HTTASHTTAS the anti-sense (backwards) version of the HTT gene levels artificially might reduce production of the harmful huntingtin proteinhuntingtin protein The protein produced by the HD gene.. That could cause beneficial effects similar to what has been seen with ‘gene silencinggene silencing An approach to treating HD that uses targeted molecules to tell cells not to produce the harmful huntingtin protein’ treatments in animal models of Huntington’s disease.

So what this work adds is another possible target: we can add ‘increasing huntingtin antisense message’ to our list of possible ways of improving the health of cells in Huntington’s disease.

This is very early-stage work that’s unlikely to lead to treatments any time soon. The more direct approaches of gene silencinggene silencing An approach to treating HD that uses targeted molecules to tell cells not to produce the harmful huntingtin protein, which we’ve written about before, will certainly be tested in human patients first.

But when it comes to developing treatments for HD, every target helps, and now there’s a new potential target: a hidden message, written backwards in our DNA.

Learn more

• Human Molecular Genetics paper describing the work (full article requires payment or subscription)
• Press release by the Margolis research group