User:AAR3643/Epigenetic regulation of neurogenesis

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We are proposing to make edits to the article Epigenetic regulation of neurogenesis. This article is rated as start-class on the article's talk page and as such there were various changes that we wished to make to improve the overall breadth of information covered by the article.  In particular, while there is relatively decent coverage of information within this article regarding epigenetic factors involved in embryonic neurogenesis, the information regarding adult neurogenesis is rather lacking in depth, and includes many topics that are essentially thrown in randomly without being discussed further or elaborated upon to paint a coherent picture.

Histone Modifications Edits: For example, one of the changes we proposed was adding an explanation of HDAC and HAT activity into the "histone modifications" subtopic within the overarching topic “Adult neurogenesis,” as well as expanding the subtopic to include more than simply the effects of histone deacetylation alone, as is present in the original article. This explanation for HDAC and HAT activity would include their overall functions of removing and adding acetyl groups to histone tails, respectively, as well as the use of HDAC inhibitors (HDACi’s) trichostatin A and valproic acid, which not only induce neuronal differentiation in embryos and lead to neurogenesis, but also inhibit the differentiation of glial cells in adult neural stem cells as well Upon reading the review article, these histone modifications and their reversal by mechanisms such as HDACs and their respective inhibitors are vital in the regulation of adult neurogenesis, and as such, we believe their inclusion within this article would be essential in ameliorating a few of its shortcomings.

miRNAs: In addition, we would also like to expand the discussions on both the miRNA and methylation-specific effects on neurogenesis, as the article discusses them briefly using only one to two sources each to support their arguments. These miRNA effects are of particular interest, seeing as researchers have discovered that less than three percent of the entire human genome encodes proteins. As a result, a great majority of the remaining genome is transcribed to a multitude of RNA’s, including miRNAs. While certain miRNAs are well-documented to play significant roles in neurogenesis and included within the current article, including both miR-9 and miR-124 which are particularly abundant in the human brain, other miRNAs including miR-137, miR-184 and miR-195 play vital functions in the proliferation of neurons in the adult hippocampus, however are not discussed in the current article .

One of the more important topics that we wish to add to this article and we believe is of utmost importance is the topic of adult neurogenesis by epigenetic reprogramming of astrocytes and other glial cells, in addition to pluripotent neural progenitor cells. This topic is only briefly discussed under the topic of “embryonic neurogenesis” and subtopic “DNA methylation,” but focuses only on the programming of astrocytes in embryonic cells, not in their ‘reprogramming’ into neuronal cells in adult neurogenesis. This inclusion should serve to highlight current knowledge within the field of this topic, and improve its overall profundity.

Epigenetic misregulation dysregulation and neurological disorders: Furthermore, we would also like to add a few more subtopics under "epigenetic misregulation and neurological disorders." The topic itself mentions epigenetic effects of Parkinson's disease, Alzheimer's disease, schizophrenia and bipolar disease, however only contains one subtopic discussing Alzheimer's disease alone. We believe that it would be beneficial for the depth of the article to include information regarding the epigenetic effects of the other diseases as well and provide subtopics for each, utilizing other sources which were note included.

For the epigenetic effects of Parkinson’s disease (PD) section, we would like to add more about how epigenetic modulation is a factor that is responsible for inducing gene expression, which in turn then regulates our development, cellular fate commitment, and adaptations to the environment-and how imbalances or changes in these areas can lead to the onset of PD: “Epigenetic modulation of gene expression by environmental factors is emerging as an important mechanism in PD and in other neurodegenerative disorders (such as the ones mentioned above). Thus, epigenetic mechanisms, such as DNA methylation, histone modifications and altered microRNA expression, have been under intense investigation due to their possible involvement in PD.”

1. for example, we could discuss how studies have shown that there are significant differences in methylation levels between healthy individuals and those with PD, which may suggest that a lack of methylation may influence or is at the very least associated with Parkinson’s, “In agreement with results in brain tissue, these studies reported a significant decrease in methylation of the SNCA promoter.”
2. beyond this, we could also discuss how PD is influenced by other epigenetic factors such as histone modifications and miRNAs.

Bipolar disorders are both highly complex and heritable, which makes it an interesting disorder to examine for epigenetic modifications. DNA methylation, DNA hydroxymethylation, and histone modifications are all capable of contributing to the formation of bipolar disorder.  For example, studies of monozygotic twins revealed that individuals with bipolar disorder had lower methylation of the peptidylprolyl isomerase E-like (PPIEL) gene, which can be attributed to the dopamine transmission. Moreover, therapeutic interventions such as engineered transcription factors could modify chromatin structure. DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors could possibly reverse epigenetic modifications in order to therapeutically address bipolar disorder.

Article body

Histone modification (edit example)

Histone acetylation, deacetylation, as well as the inhbition of histone deacetylation mechanisms also play large roles in the proliferation and self-renewal of post-natal neural stem cells, in contrasting ways. Neural-expressed HDACs interact with Tlx, an essential neural stem cell regulator, to suppress TLX target genes. This includes the cyclin-dependent kinase inhibitor P21 and the tumor suppressor gene Pten to promote neural stem cell proliferation. The most prominently studied and well-understood regulators of chromatin remodeling, which play an important role in adult neurogenesis are histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs add acetyl groups to nucleosomes, while HDACs remove them. The acetylation of histones leads to decreased condensation of the nucleosomes to target DNA, and increases the likelihood that gene expression may occur by freeing up the DNA targets to bind to their respective transcriptional factors. This process is involved in neural proliferation regulation, as different neuronal cell genes are expressed and repressed. Deacetylation of histones leads to the reverse, and increases the likelihood for the repression of gene expression. HDAC inhibitors (HDACi), such as valproic acid (VPA) and trichostatin A can promote proliferation of adult neurogenesis through the reversal of HDAC activity, inducing differentiation of adult progenitor cells. Inhibition of HDACS by the antiepileptic drug valproic acid induces neuronal differentiation as in embryonic neurogenesis, but also inhibits glial cell differentiation of adult neural stem cells. This is likely mediated through upregulation of neuronal specific genes such as the neurogeneic basic helix-loop-helix transcription factors NEUROD, NEUROGENENIN1, and Math1. Conditional loss of HDAC1, HDAC2 in neural progenitor cells prevented them from differentiating into neurons and their loss in oligodendrytic progenitor cells disrupted oligodendrocyte formations, suggesting that histone deacetlyation plays important but varying roles in different stages of neuronal development.

References

*note: source 9 below is from the original article, included to cite the information already present within the article*