User:Courtney Pinard/Neuroepigenetics

'''You have good ideas here. However, it time to turn it into real text. Copy out parts of the original article above and below any text you will add. Then underline all of your new text so that I can find it. Time to stop outlining and start writing! I will not evaluate at outline at this time. I need to see this in a copy of the actual article.'''

Ideas for Neuroepigenetics Article Improvement
This article should include the following information:

1. DNA demethylation and memory/learning: There is currently a section on methylation but even in the final sentences this section lacks a broader overview of how DNA demethylation is significant for learning and memory. The description of DNA methylation regulation needs to be specified as an active process and possibly carry this explanation out to include details about its significance at different stages of CNS development. This section of the article should also begin to mention hmC's role in active demethylation. The article currently uses majority of this section describing DNMTs and glucocorticoid receptors but should possibly also include information on TET family of enzymes (details of relationship is also a discovery of Song's lab).


 * DNA demethylation - Wikipedia needs to be sited under this section addition as it is discussed in more detail on this page along with TET family genes

2. Histone acetylation/deacetylation and phosphorylation: This is a mechanism that should be added since there is a significant amount of research being done on the pharmacological potential of HDAC inhibitors' use in treatment of neurological conditions, and there are several phosphatases involved histone modification within the nervous system. One important mechanism explored so far in this epigenetics course has been the role of HDAC2 inhibitors in restoring memory formation and the roles of HDACs in learning and memory pathways. We could expand on these concepts more in this article as it pertains to Neuroepigenetics.


 * Histone deacetylase - Wikipedia needs to be sited under this section addition as it is discussed in more detail on this page including some implications for treatment for psychiatric conditions.
 * Histone acetylation and deacetylation - Wikipedia This page could also be sited to include a more general overview of the histone acetylation/deacteylation mechanisms as well as histone phosphorylation.

3. (Information for the introductory paragraph) Background information about the significance of epigenetic mechanisms in the nervous system on the basis of non-dividing neurons lacking the property of heritability.

4. Explanation for how regulation of neuronal gene expression may be a consequence of non-coding RNAs.


 * Non-coding RNA - Wikipedia This page goes into a bit more detail on what non-coding RNAs are and touches on how they are related to Alzheimer's Disease but doesn't go into too much detail about this.

5. The Mechanisms section of this article lists some Neuroepigenetic mechanisms that are not explained in further sections such as prions and L1 elements carrying the potential to manipulate neuronal plasticity. This section also mentions REST but does not include information about NRSE or information regarding their relevance in developing the nervous system.

6. The Neuro-oncology section does not include information about the use of BrdU cancer treatment resulting in evidence of neurogenesis. This information should be included since there is currently a considerable amount of research being conducted to study the epigenetics of neurogenesis. (Expand on this idea of epigenetics of neurogenesis a bit more)


 * Neurogenesis - Wikipedia

7. The article currently does not include information on the study of maternal mice nurturing and the subsequent generation's DNA methylation and behavioral expressions. This is a major research contribution for the justification of epigenetic mechanisms involved in the nervous system and the persistence of these mechanisms in the adult brain.

8. The Neurodegenerative diseases section only includes two examples and could probably be expanded to include other cognitive disorders such as Schizophrenia, Rett syndrome, etc.


 * Neurodegenerative disease - Wikipedia This page details more aspects of neurodegeneration and some epigenetic mechanisms behind the process.
 * Rett syndrome - Wikipedia More information about Rett syndrome in general. Plan to discuss MeCP2 as a HDAC recruiter.
 * MECP2 - Wikipedia
 * Schizophrenia - Wikipedia More information about Schizophrenia in general. Plan to discuss Reelin involvement in synapse formation.
 * Reelin - Wikipedia
 * Rubinstein–Taybi syndrome - Wikipedia. Plan to discuss CREB-binding protein (CBP) as a histone acetyltransferase.
 * CREB-binding protein - Wikipedia
 * Fragile X syndrome - Wikipedia. Plan to discuss trinucleotide extensions for FMR1 & 2 genes as a mechanism of increasing DNA methylation and decreasing histone acetylation leading to this disorder.
 * FMR1 - Wikipedia
 * Alzheimer's disease - Wikipedia Plan to discuss amyloid precursor protein involvement in increased histone acetylation.
 * Amyloid-beta precursor protein - Wikipedia

9. Research Section: Mention the work of Hongjun Song and use of DNA repair mechanisms in the demethylation of mature neurons and its significance in redefining epigenetics to encompass neuroscience. Active histone subunit exchange involvement in the nervous system is also a newer area of study that should probably be explained or sited. The research section should also include a smoother transition from discussing cognitive disorders by referencing emerging research regarding each of them distinctly.

PDF Links
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Article Improvement Draft
(Include this in 'Mechanisms' section under 'Methylation')

Active DNA Demethylation
Research studies exploring the dynamic regulation of DNA demethylation have ascertained several molecular modulators that promote cognitive function and neuroplasticity. Observation of DNA methylation states during embryonic development outlined mitotically independent parental genome demethylation and remethylating events in the fetus in subsequent developmental stages, a finding indicative of active DNA demethylation contributions in mature neurons. By examining the molecular cascades of methyl-cytosine (mC) cycling, evidence defines DNA base-excision repair, modulated by Gadd45, as a means for demethylating neurons. Additionally, TET-family enzymes are active DNA demethylation initiators and manipulation of Tet gene expression is currently being studied for possible epigenetic therapeutics for individuals with cognitive deficiencies. Through the process of demethylation, there is potential for reversal of gene silencing, like activating the memory-promoting gene known as Reelin. Induced demethylation of BDNF and FGF-1 promoters using electroconvulsive stimulation proved the significance of active DNA demethylation in neurogenesis and further outlined the participation of Gadd45 as a regulatory unit for this mechanism.

Tet Proteins
Ten-eleven translocation 1 (TET1) genes have been known to be involved in the regulation of activity-dependent molecular cascades leading to an array of gene expression, the magnitude and frequency of excitatory postsynaptic potential propagation involved in synaptic transmission, and cognitive capability by initiating active DNA demethylation. As such, this gene family has been thoroughly examined to further understand the specific mechanisms involving their isoforms in central nervous system processes that could lead to improvements in treatment techniques regarding cognitive impairment. The isoform Tet1S, or the short transcript with a truncated N-terminus, is the more predominantly expressed Tet1 isoform and is associated with neuronal expression. The isoform Tet1FL, or the traditional full-length transcript for Tet1, is more prevalent in glial cells as opposed to neurons, however, research found that suppression its expression in mice was correlated with hippocampal-dependent memory impairment. In contrast, research determined that repressing Tet1S gene expression resulted in improvements of hippocampal-dependent memory through an increase in the presentation of fear behavior during contextual fear conditioning experiments in mice. Using genetically engineered TALEs for Tet1 isoforms including SID4X inhibitory sequence, researchers were able to associate Tet1FL acute repression with enhancement of off-target gene activation involving inflammatory response cascades, while acute repression of Tet1S was associated with synaptic plasticity gene pathway amplification. Tet2 genes have been explored as negative regulators of neuroplasticity as they are heavily expressed across the brain and manipulations in expression have been linked to improvements of spatial memory. Tet3 genes are studied in pathways involving cognitive function since they are the most abundantly expressed Tet family gene in the brain. Studies determined that down-regulation of Tet3 produced significant changes in synaptic transmission, while silencing its expression declined behavioral responses associated with spatial memory formation.

Histone Deacetylation
The expression of HDAC genes is of interest to the scientific community as the regulation of their associated isoforms proves especially relevant in associative learning and memory formation. Histone deacetylation consequently results in decreased gene expression in pathways involving synaptic plasticity and synaptogenesis.

HDAC1

HDAC2

HDACi (inhibitors)