Regulation of Adult Neurogenesis: From Epigenetics to Behavior

Abcam

Highlights

Abcam’s Regulation of Adult Neurogenesis Meeting was held on July 12-13th 2012. Dale Bryant from King’s College London was on hand for the proceedings and sent back this report covering the highlights from Barcelona, Spain.

Regulation of Adult Neurogenesis Overview

The conference took place in the Casa Convalescència located in the grounds of the Hospital de la Santa Creu i Sant Pau. The speakers presented their work in the Aula Magna, a former chapel with a dome of stained glass windows lighting the room from above the hall. The presentations covered all aspects of neurogenesis from genetics to cognition and behaviour. All of the speakers gave very interesting talks and below are summaries of the presentations that included an element of epigenetics.

The conference was planned to begin with a presentation by Magdalena Götz on chromatin remodelling however she was unable to attend so Gerd Kempermann kicked off the day instead.

Systems Genetics of Adult Neurogenesis

Gerd Kempermann, Centre for Regenerative Therapies Dresden & German Centre for Neurodegenerative Diseases

Dr. Kempermann began by describing how adult neurogenesis is a highly polygenic trait. Many genes appear to play a role while individual genes only explain a little of the variance found in populations. He believes that we must be very cautious when interpreting correlations between gene expression and phenotype. This is particularly relevant to hippocampal neurogenesis where dense networks of genes surround the transcriptional network of interest. He described this as a small world, scale free network:

Small world: Because there are only ever a few steps between all genes in the network. He mentioned that there are only ever three steps (or “three degrees”) between any gene and a gene involved in adult neurogenesis.

Scale free: Because some genes show greater connectivity to other genes than others. By looking at the strength of relationships between these genes it is clear that there are a few genes that appear to have more important relationships within the network.

The approach of Kempermann’s group was to look at the covariance between expression data and phenotype to identify genes with important roles in adult neurogenesis. To do this they used 20 primary stem cell lines derived from different mice of the same population. Despite being derived from similar mice there was phenotypic variability between the lines. This allows the group to look at transcriptome data across the cell lines and see how this co-varies with phenotype. From this data his group were able to generate networks of potentially regulated genes which they could then investigate further. Using this method they identified a gene called Lrp6 whose expression co-varied with proliferation. Lrp6 is a co-receptor for Wnt signalling so it is unsurprising to see that it may play a significant role in neurogenesis.

Another interesting aspect of Kempermann’s presentation was his mention of a database he has been part of designing. The database called ‘The Mammalian Adult Neurogenesis Gene Ontology’ (abbreviated MANGO) is an automated system that tracks publications related to genes mapped to cell types and processes – only in relation to adult neurogenesis. As the name suggests, this database has fewer genes than a typical gene ontology database but because of its specificity it should prove more reliable when looking at adult neurogenesis. The database can be found at www.adult-neurogenesis.de.

Epigenetic Mechanisms in Neuropsychiatric Diseases

André Fischer, European Neuroscience Institute

Dr. Fisher began with descriptions of studies showing that monozygotic twins have increasing differences in DNA methylation and histone acetylation patterns with increasing age. The number one risk factor for the majority of diseases is aging and these disorders likely appear as a result of changes in gene expression. Because of this, Fischer is asking whether these processes are epigenetically regulated.

Fischer outlined how epigenetic dysregulation is a characteristic of a number of neurological diseases. Environmental enrichment leads to beneficial effects in most or all disease models and results indicate this is relevant to humans. He believes that environmental enrichment is likely regulated by epigenetic mechanisms. It has been shown that environmental enrichment regulates plasticity at least in part through histone acetylation which in turn activates gene expression programs. The hope is that there are drugs that have similar regulatory effects. In support of this idea, there are reports that histone deacetylase (HDAC) inhibition has beneficial effects on cognitive function by increasing histone acetylation.

He discussed findings from his research that have shown that histone acetylation levels are associated with age related memory impairment in mice. He is specifically interested in histone 4 lysine 12 acetylation (H4K12Ac), a histone modification largely localised to the coding region of genes. Fischer’s group has found that H4K12Ac levels respond to learning tasks in 3 month old mice. In contrast, H4K12Ac levels are unaffected by the same tasks in 16 month old mice. HDAC inhibitors that increase H4K12Ac levels reinstate memory and the associated gene expression profile in the older mice. The HDAC inhibitors that do not affect H4K12Ac levels are less able to do this. Fischer noted that these findings are consistent with reports from Li-Huei Tsai’s group that show memory is affected by HDAC2 activity and that levels of HDAC2 correlate with the amount of H4K12Ac (Guan et al., Nature 2009). He argues that deregulation of H4K12Ac is at least in part behind age associated memory impairment.

Throughout this presentation it was clear that Fischer is confident that epigenetics will become increasingly useful as biomarkers and strategies for disease.

Stress Hormone Exposure in Adult Hippocampal Neurogenesis

Carlos Fitzsimons, University of Amsterdam

Dr. Fitzsimons’s work has looked at how glucocorticoids regulate adult neurogenesis. During stress, glucocorticoid levels increase and this has been shown to inhibit neurogenesis. In the adult hippocampus this appears to happen via activation of glucocorticoid receptors on neural stem cells.

As part of their investigations, the Fitzsimons group has studied the response of neural stem cells to glucocorticoid stimulation in vitro. Dexamethasone (DEX) is a drug that activates the glucocorticoid receptor so it can be used to study the effects of glucocorticoids on neural stem cells. As with the effects of glucocorticoids, treatment with DEX inhibits proliferation without effecting cell death as measured by caspase-3 activity. He described this as a possible transition of neural stem cells to a quiescent (i.e. non/slow proliferating) phenotype.

He reports that his group has shown that the effects of DEX on proliferation are reversible. He showed that washing away the drug returns proliferation to normal levels. When looking for effects of DEX treatment on gene expression, one particular gene to respond was Dicer expression – Dicer is a key component of the microRNA biogenesis pathway. Fitzsimons was eager to point out that the quiescent phenotype in response to DEX treatment may not be fully reversible as there seemed to be a strong sensitisation to subsequent future exposure. Notably the effect on Dicer expression was greater on the second exposure to DEX. Interestingly he also mentioned that DEX treatment has been shown to lead to a global decrease in DNA methylation.

Based on these observations, Fitzsimons suggests that glucocorticoids may act as a “pacemaker of proliferation”. He is now asking whether the response to stress on neurogenesis is damaging or protective? Are the effects beneficial or detrimental to the individual? He speculates that the response to stress on neurogenesis could be beneficial as it may be preserving the stem cell pool rather than promoting the differentiation of these cells.

Regulation and Function of Adult Neurogenesis in the Dentate Gyrus

Fred Gage, The Salk Institute

Part of Dr. Gage’s talk focused on long interspersed element type 1 (LINE-1 or L1), a family of retrostransposons that integrate themselves into the genome. His lab has shown that L1 insertions can affect the expression levels of certain genes by using the response of synaptic gene Psd-93 as an example. Using a reporter construct he calls “Jump and Glow” they have tracked L1 insertions, finding that they are largely specific to neural cells. Further experiments showed that around half of these insertions land in neuronal associated genes. He describes how there are regional differences within the brain regarding the level of L1 insertions. However despite these differences, the number of insertions in brain areas is always higher than the number of insertions observed in heart or liver.

L1 retrostransposition is not an epigenetic mechanism itself as it results in changes to the DNA sequence. However research from the Gage lab has shown that epigenetic mechanisms regulate L1 retrotansposition. He has shown that L1 activity is controlled by the activity of the epigenetic factor HDAC1 and more specifically MeCP2, a protein that binds to methylated DNA. He then went on to mention how this may have implications for Rett syndrome, a neurodevelopmental condition most frequently caused by mutations in the MeCP2 gene. Indeed, there appears to be an increase in retrotransposon activity in cells generated from Rett syndrome patients.

Most interesting was his ideas as to the reason for these L1 insertion events, particularly in neurons. He said that L1 insertions may introduce variance into somatic genomes – variation in the genomic DNA sequence of individual cells. In response to questions Professor Gage went to efforts to stress that he was not suggesting that L1 insertions target particular genes but rather he believes that they are random insertions. He speculates that this generation of genomic diversity between neurons could expand the amount of behavioural diversity within a population. This seems to be a very interesting hypothesis, which I am sure his group will try to address.

Summary

The intention of the conference was to look at aspects of adult neurogenesis across all the subject areas surrounding this process. Because of this, epigenetics was only part of the discussion however it was interesting to see how groups are integrating work in this area with other fields to better understand how adult neurogenesis is regulated. Dysregulation of adult neurogenesis is a phenotype of a number of diseases and the causes of this are at least in part a result of changes in gene expression. Therefore the presentations gave a promising indication of how the work of these and other research groups will uncover which epigenetic factors may be important therapeutic targets for the future.

**EpiGenie thanks Dale Bryant, who is a PhD student at King’s College London, School of Medicine, for providing this conference coverage.