Researchers map epigenetic pathway of neurogenesis in the hippocampus.


Newborn neurons generated from neural progenitor cells in a brain region called the hippocampus play an important role in learning and memory in adults. However, the molecular mechanisms that control this neurogenesis process have not been fully understood. Sanford-Burnham researchers recently shed new light on this question by discovering a key role of a protein called SOX2 in neuronal development. As reported in Proceedings of the National Academy of Sciences, SOX2 promotes the activation of genes involved in differentiation, enabling neural progenitor cells to turn into mature neurons in the brains of adult mice.

The team state that although SOX2 is arguably a cornerstone of neural stem cell biology and plays an essential role in neurogenesis in the developing and adult brain, the mechanisms by which this protein regulates neuronal differentiation have remained unclear until now.  Understanding the fundamental mechanism of SOX2 function may inspire the design of pharmacological approaches to enhance adult neurogenesis as well as shed light on the potential function of SOX2 in cancer stem cells.

Previous studies have shown that SOX2 is a marker of neural stem and progenitor cells, and its function is required for the self-renewal of these cells. SOX2 mutations are associated with defective hippocampal development and seizures in humans and impaired neurogenesis in the adult mouse brain. However, the molecular mechanisms underlying the function of SOX2 in adult neurogenesis were previously unknown. Past research has suggested that SOX2 binds to the regulatory regions of hundreds of genes involved in neuronal differentiation and represses their activity, but it has not been clear whether the protein might also contribute to the activation of these genes.

In the current study the team found that SOX2 deficiency in neural progenitor cells in the hippocampus of adult mice reduced the activation of genes that are essential for neuronal differentiation. As a result, many new neurons died before maturation, while surviving newborn neurons had structural abnormalities and displayed unusual activity. SOX2 binds to the regulatory regions of these genes, called Ngn2 and NeuroD1, and prevents the accumulation of a gene-silencing epigenetic mark called H3K27me3.

Taken together, the data findings suggest that SOX2 promotes a poised epigenetic state at the regulatory regions of neurogenic genes, thereby enabling neural progenitor cells to turn into mature neurons upon exposure to molecular cues that trigger differentiation.

On a clinical note, the neuronal defects observed in the hippocampus of adult mice in the current study may contribute to the learning and intellectual disabilities experienced by patients with a rare disorder called SOX2 anophthalmia syndrome.  The team explain that given the reversibility of epigenetic changes the results suggest that pharmacological therapies directed at restoring the levels of neurogenic genes down-regulated in SOX2-deficient neural progenitor cells in the hippocampus might be beneficial for anophthalmia syndrome patients, particularly in ameliorating hippocampal-related learning disability.

Moving forward, the researchers will continue to investigate the newly discovered function of SOX2 and the impact of SOX2 deficiency on hippocampus-dependent learning and memory tasks. They will also identify other factors involved in the epigenetic regulation of differentiation genes by elucidating pathways and mechanisms of action downstream of SOX2 on the whole-genome scale.

Another clinically relevant research direction state the team will be to further explore the role of SOX2 in cancer. Past research has shown that this protein maintains cancer stem cells, drives tumor initiation, and promotes resistance to cancer drugs. The mechanisms of SOX2 function that the researchers discovered are likely to apply to other tissue stem cell compartments as well as to multiple types of cancer that overexpress SOX2 in cancer stem cells.

The team are currently using their findings to develop small-molecule inhibitors of cancer stem cells for the treatment of glioblastoma multiforme, a fast-growing type of malignant brain tumour that is the most common brain tumour in adults. The researchers state that because there are currently no effective long-term treatments for this disease, patients have a poor prognosis and usually survive less than 15 months following diagnosis.  They go on to surmise that therapies which target SOX2 activity in cancer stem cells offer promise for eradicating these aggressive brain tumours and dramatically improving clinical outcomes for patients.

Source:  Sanford-Burnham Medical Research Institute

Epigenetic Regulation of SOX2 at the Promoters of Poised Genes in Adult Hippocampal NPCs.  Adult hippocampal NPCs (purple cells) in wild-type mice generate neuroblasts and newborn neurons (green cells) that integrate in the DG. In NPCs SOX2 binds to the promoters of poised genes and limits the activity of the PRC2 complex (H3K27me3), enabling proper gene expression (active chromatin) in the neuroblasts. In SOX2 mutants the binding of EZH2 and PRC2 activity (repressive chromatin mark, H3K27me3) are increased at the promoters of poised proneural and neurogenic genes. Consequently, transcriptional activation of poised genes (e.g. Ngn2, NeuroD1, Sox21, Bdnf, Gadd45b) is reduced in SOX2 mutants resulting in increased neuroblasts apoptosis and altered morphology and function of newborn DG neurons.  SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis.   Terskikh et al 2015.

Epigenetic Regulation of SOX2 at the Promoters of Poised Genes in Adult Hippocampal NPCs. Adult hippocampal NPCs (purple cells) in wild-type mice generate neuroblasts and newborn neurons (green cells) that integrate in the DG. In NPCs SOX2 binds to the promoters of poised genes and limits the activity of the PRC2 complex (H3K27me3), enabling proper gene expression (active chromatin) in the neuroblasts. In SOX2 mutants the binding of EZH2 and PRC2 activity (repressive chromatin mark, H3K27me3) are increased at the promoters of poised proneural and neurogenic genes. Consequently, transcriptional activation of poised genes (e.g. Ngn2, NeuroD1, Sox21, Bdnf, Gadd45b) is reduced in SOX2 mutants resulting in increased neuroblasts apoptosis and altered morphology and function of newborn DG neurons. SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis. Terskikh et al 2015.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s