Saturday, March 3, 2012

Take two HDAC inhibitors and call me in the morning

Changes in the environment, either at the level of cells, or on an organismal scale, can activate enzymes that chemically modify the DNA or DNA-associated proteins in such a way that gene expression is altered. For instance, it’s been shown that parental neglect of young mice, causes a number of their genes to be turned off via epigenetics. In this week’s paper, published online in Nature, the authors make a link between Alzheimer’s Disease, epigenetics and widespread decreased expression of genes that are important for cognitive function and learning. 

Histone Acetylation
The first thing that you need to understand is the connection between histone acetylation and gene expression.

Question 1: What is a histone?
We have 46 chromosomes in every cell and each chromosome is made up of a very, very, very long strand of DNA. Think about what happens to your electrical cords and chargers and headphones when you throw them all into a drawer: all the wires get wrapped up together and twisted into knots. That could happen to our long strands of DNA, which would be a disaster. Luckily, our cells are super organized and wrap sections of DNA around spools of histone proteins. This is sort of like the tabs on a Mac charger, around which you can wrap the extra cord. The DNA wraps two times around each core of histones and then spans to the next histone and wraps around two times, etc. The histones help keep the DNA organized, but they also act as a way to control DNA expression.

Question 2: What is acetylation?
An acetyl group is a small chemical group (-COCH3) that can be added to larger molecules by enzymes. The histone proteins have tails that hang out and which can be acetylated in a dynamic process.

Question 3: What does this have to do with gene expression?
If the DNA wraps around the histones very tightly, the protein machinery that expresses DNA cannot get access to the DNA and gene expression is turned off. This is one way that histones can control DNA expression. When histones become acetylated, the DNA loosens its grip on the histones, so there is plenty of room for proteins to bind DNA and gene expression is turned on.

+ Acetyl = active genes
- Acetyl = inactive genes

Question 4: What adds acetyls to histones?
Enzymes called Histone Acetyl Transferases (HAT) add acetyl groups, and enzymes called Histone Deacetylases (HDAC) take off acetyls. If you have a high level of HDACs around, they will take off lots of acetyls, DNA will wrap tightly around histones and gene expression will be turned off (see top part of figure below. Figure from Pons et al., 2009, European Heart J)

Increased HDAC --> - Acetyl --> tightly wrapped DNA --> inactive genes

HDAC in Alzheimer’s model
The authors investigated the role histone acetylation may play during the progression of neurodegeration associated with Alzheimer’s Disease (AD). A major aspect of AD is the accumulation of protein aggregates in the brain made up of amyloid beta (amyloid plaques). There are mouse models of AD which have these amyloid plaques, neurodegeneration (their brain cells die) and cognitive defects. The authors measured levels of different HDACs in one of the AD mouse models and found that HDAC2 was greatly overexpressed in the brain compared to control mice. As would be expected, histone acetylation was reduced (remember they take off acetyl groups from histones). They next looked at the expression levels of genes that have been implicated in the process of learning and memory. When we learn something, certain genes are activated in nerve cells, which can lead to long lasting changes to the functioning of the cells (maybe they will become easier to activate or maybe the cell will make more synaptic connections with other nerves). Gene expression was reduced, which may be one reason for the cognitive defects associated with AD.

Restoring cognition
To summarize, there is more HDAC2 around in AD mice, so there is less histone acetylation and gene expression is decreased. The authors reasoned that perhaps they could restore the ability of these mice to learn and remember if they could stop the increase in HDAC2. In mice and other experimental organisms, you can lower expression of any gene of interest by expressing what’s called inhibitory RNA (RNAi) for that gene. This is basically the complementary sequence of that gene (which is DNA) in the RNA format. What’s important here is that the authors made a RNAi for HDAC2 and stuck it in a virus which was used to get this molecule into the mouse brain. The RNAi did its job and brought the levels of HDAC2 in AD mice back down to a normal level. Expression of the “learning” genes was restored and their neurons made more synaptic connections than the AD mice with high HDAC2. Interestingly, the RNAi wasn’t able to reverse the neurodegeneration; once the neurons die in AD mice, they are dead forever. However, the fact that their remaining neurons made more synaptic connections was a good sign that learning could happen again. The authors set up a series of different learning tasks for the mice, and the RNAi mice with normal levels of HDAC2 performed as well as the controls, whereas the AD mice with high HDAC2 underperformed.

Being able to rescue cognitive defects in AD mice by simply altering the levels of a histone deacetylase is pretty amazing. It shows that the AD mice brains are still capable of learning and of growing more synapses, but they are constrained by the gene expression block imposed by HDAC2. This would be a good direction to go when investigating new treatments for Alzheimer’s Disease. In fact, the authors looked at tissue from human brains and found that patients who died from AD had increased HDAC2 protein expression compared to healthy controls. This is a good indication that what worked in the mouse model could also work in humans.

Besides this, the authors did a whole set of experiments to show what causes the HDAC2 overexpression in the first place. Remember that one of the main causes of AD is protein aggregation, or amyloid plaques. These big globs of proteins stress out the cells, which may activate different protein pathways to try to deal with the situation. One of the proteins that is turned on is called GR1 which activates expression of the HDAC2 gene. Basically, the cell is freaking out and tries to help, but HDAC2 overexpression is actually bad and prevents neurons from learning.

Stressed cell --> GR1 --> HDAC2 gene expression --> less histone acetylation --> compact DNA --> inactive genes --> inability of cell to grow synapses --> no learning

This paper was ridiculously thorough. Whereas most papers would have stopped at restoring cognition (this has big implications), the authors kept going on to describe the whole signaling pathway. And to think, it all has to do with epigenetics and little acetyl groups of histones. Amazing!

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