Archive for the ‘HDACs’ Category

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from Ye et al., 2009:

HDAC1/2 genes encode proteins that modify the epigenome (make it less accessible for gene expression).

When HDAC1/2 functions around the HES5 and ID2/4 (repressors of white matter development) genes, the epigenetic changes (less acetylation of chromatin) helps to repress the repressors.

This type of epigenetic repression of gene expression (genes that repress white matter development) is essential for white matter development.

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The cognitive and emotional impairments in the autism spectrum disorders can be difficult for parents and siblings to understand and cope with.  Here are some graphics and videos that might assist in understanding how genetic mutations and epigenetic modifications can lead to various forms of social withdrawl commonly observed in the autism spectrum disorders in children.

In this post, the focus is just on the MecP2 gene – where mutations are known to give rise to Rett Syndrome – one of the autism spectrum disorders.  I’ll try and lay out some of the key steps in the typical bare-bones-link-infested-blogger-fashion – starting with mutations in the MecP2 gene.  Disclaimer: there are several fuzzy areas and leaps of faith in the points and mouse model evidence below, and there are many other genes associated with various aspects of autism spectrum disorders that may or may not work in this fashion.  Nevertheless, still it seems one can begin to pull a mechanistic thread from gene to social behavior Stay tuned for more on this topic.

1. The MecP2 gene encodes a protein that binds to 5-Methylcytosine – very simply – a regular cytosine reside with an extra methyl group added at position 5.  Look at the extra -CH3 group on the cytosine residue in the picture at right.  See?  That’s a 5-methylcyctosine residue – and it pairs in the DNA double helix with guanosine (G) in the same fashion as does the regular cyctosine reside (C). 5methC OK, now, mutations in the gene that encode the  MecP2 gene – such as those found at Arginine residue 133 and Serine residue 134 impair the ability of the protein to bind to these 5-Methylcyctosine residues.  bindingMecP2The figure at left illustrates this, and shows how the MecP2 protein lines up with the bulky yellow 5-Methylcytosine residues in the blue DNA double helix during binding.

2. When the MecP2 protein is bound to the methylated DNA, it serves as a binding site for another type of protein – an HDAC or histone deacetylase. The binding of MecP2 and HDAC (and other proteins (see p172 section 5.3 of this online bookChromatin Structure and Gene Expression“)).  The binding of the eponymously named HDAC’s leads to the “de-acetylation” of proteins known as histones.  The movie below illustrates how histone “de-acetylation” leads to the condensation of DNA structure and repression or shutting down of gene expression (when the DNA is tightly coiled, it is inaccessible to transcription factors).  Hence: DNA methylation leads (via MecP2, HDAC binding) to a repression on gene expression.

3. When mutated forms of MecP2 cannot bind, the net result is MORE acetylation and MORE gene expression. As covered previously here, this may not be a good thing during brain development since more gene expression can induce the formation of more synapses and – possibly – lead to neural networks that fail to grow and mature in the “normal” fashion. The figure at right toomanysynapsessuggests that neural networks with too many synapses may not be appropriately connected and may be locked-in to sub-optimal architectures.  Evidence for excessive synaptogenesis is abundant within the autism spectrum disorders.  Neuroligins – a class of genes that have been implicated in autism are known to function in cell & synaptic adhesion (open access review here), and can alter the balance of excitation/inhibition when mutated – which seems consistent with this heuristic model of neural networks that can be too adhesive or sticky.

4. Cognitive and social impairment can result from poor-functioning neural networks containing, but not limited to the amygdala. The normal development of neural networks containing the forntal cortex and amygdala are important for proper social and emotional function.  The last piece of the puzzle then would be to find evidence for developmental abnormalities in these networks and to show that such abnormalities mediate social and/or emotional function.  Such evidence is abundant.

Regarding the effects of MecP2 however, we can consider the work of Adachi et al., who were able to delete the MecP2 gene – just in the amygdala – of (albeit, an adult) mouse.  Doing so, led to the disruption of various emotional behaviors – BUT NOT – of various social interaction deficits that are observed when MecP2 is deleted in the entire forebrain.  This was the case also when the team infused HDAC inhibitors into the amygdala suggesting that loss of transcriptional repression in the adult amygdala may underlie the emotional impariments seen in some autism spectrum disorders.  Hence, such emotional impairments (anxiety etc.) might be treatable in adults (more on this result later and its implications for gene-therapy).

Whew!  Admittedly, the more you know – the more you don’t know.  True here, but still amazing to see the literature starting to interlink across human-genetic, mouse-genetic, human-functional-imaging levels of analysis. Hoping this rambling was helpful.

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The homunculus (argument) is a pesky problem in cognitive science – a little guy who might suddenly appear when you propose a mechanism for decision making, spontaneous action or forethought  etc. – and would take credit for the origination of the neural impulse.  While there are many mechanistic models of decision making that have slain the little bugger – by invoking competition between past experience and memory as the source of new thoughts and ideas – one must always tread lightly, I suppose, to be wary that cognitive mechanisms are based completely in neural properties devoid of a homuncular source.

Still, the human mind must begin somewhere.  After all, its just a ball of cells initially, and then a tube and then some more folds, layers, neurogenesis and neural migration  etc. before maturing – miraculously – into a child that one day looks at you and says, “momma” or “dada”.  How do these neural networks come into being?  Who or what guides their development toward that unforgettable, “momma (dada)” moment?  A somewhat homuncluar “genetic program” – whose instructions we can attribute to millions of years of natural selection?  Did early hominid babies say “momma (dada)?  Hmmm. Seems like we might be placing a lot of faith in the so-called “instructions” provided by the genome, but who am I to quibble.

On the other hand, you might find that the recent paper by Akhtar et al., “Histone Deacetylases 1 and 2 Form a Developmental Switch That Controls Excitatory Synapse Maturation and Function” [doi:10.1523/jneurosci.0097-09.2009] may change the way you think about cognitive development.  The team explores the function of two very important epigenetic regulators of gene expression – histone deacetylases 1,2 (HDAC1, HDAC2) on the functionality of synapses in early developing mice and mature animals.  By epigenetic, I refer to the role of these genes in regulating chromatin structure and not via direct, site-specific DNA binding.  The way the HDAC genes work is by de-acetylating – removing acetyl groups – thus removing a electrostatic repulsion of acetyl groups (negative charge) on histone proteins with the phosphate backbone of DNA (also a negative charge).  When the histone proteins carry such an acetyl group, they do NOT bind well to DNA (negative-negative charge repulsion) and the DNA molecule is more open and exposed to binding of transcription factors that activate gene expression.  Thus if one (as Akhtar do) turns off a de-acetylating HDAC gene, then the resulting animal has a genome that is more open and exposed to transcription factor binding and gene expression.  Less HDAC = more gene expression!

What were the effects on synaptic function?  To summarize, the team found that in early development (neonatal mouse hippocampal cells) cells where the HDAC1 or 2 genes were turned off (either through pharmacologic blockers or via partial deletion of the gene(s) via lentivirus introduction of Cre recombinase) had more synapses and more synaptic electrical activity than did hippocampal cells from control animals.  Keep in mind that the HDACs are located in the nucleus of the neuron and the synapses are far, far away.  Amazingly – they are under the control of an epigenetic regulator of gene expression;  hence, ahem, “epigenetic puppetmasters”.  In adult cells, the knockdown of HDACs did not show the same effects on synaptic formation and activity.  Rather the cells where HDAC2 was shut down showed less synaptic formation and activity (HDAC1 had no effect).  Again, it is amazing to see effects on synaptic function regulated at vast distances.  Neat!

The authors suggest that the epigenetic regulatory system of HDAC1 & 2 can serve to regulate the overall levels of synaptic formation during early cognitive development.  If I understand their comments in the discussion, this may be because, you don’t necessarily want to have too many active synapses during the formation of a neural network.   Might such networks might be prone to excitotoxic damage or perhaps to being locked-in to inefficient circuits?  The authors note that HDACs interact with MecP2, a gene associated with Rett Syndrome – a developmental disorder (in many ways similar to autism) where neural networks underlying cognitive development in children fail to progress to support higher, more flexible forms of cognition.  Surely the results of Akhtar et al., must be a key to understanding and treating these disorders.

Interestingly, here, the controller of these developmental phenotypes is not a “genetic program” but rather an epigenetic one, whose effects are wide-spread across the genome and heavily influenced by the environment.  So no need for an homunculus here.

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TATA-binding protein (TBP) recognizes TATA seq...Image via Wikipedia Siming Shen et al., in their paper, Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency provide insight on basic mechanisms of myelination. While myelination (think of it as the plastic insulation on copper electrical wires) makes normally developing neural networks much more efficient, it has a way of inhibiting the re-development and repair of mature neural circuits. The research team shows that recruitment of histone deacetylases (HDACs) is rather inefficient in mature oligodendrocytes precursor cells (the cells that adhere to bare neuronal axons and form the insulating myelin-rich sheath) in contrast to younger cells which differentiate readily. HDAC1 and HDAC2 are shown to down-regulate of Hes5 and Sox2, which have previously been implicated in blocking the differentiation of stem cells to oligodendrocytes. Here, the term ‘epigenetic’ refers to the mechanism of gene regulation – not by way of transcription factors binding to specific sequences – but rather, by factors being sterically blocked from binding by the 3-dimensional superstructure of the chromosome that occurs when histone proteins are deacetylated. The team suggests that as the brain ages, it becomes more difficult to recruit HDAC1,2 to the promoters needed to shut down the expression of the differentiation inhibitors. The results pose a confound for the certain applications of inhibitors of histone deacetylases (HDACi) which have demonstrated anti-tumor activity – but may – as suggested by this article – have negative consequences on brain repair processes.

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