User:Ericgarika/Article1mprovement

Sandbox of Adilyn Voss, Patricia Tomacruz, Eric Garcia

Trevor's comments in magenta

We have attached a similar format onto Adilyn Voss' sandbox; we weren't sure whether to propose a new article or add to this one, therefore we did both to make sure. The information is the same.

Please tell me that this has not continued. Just one and only one sandbox should be actively developed. Please, right now make this your only sandbox and incorporate the information from the other sandbox here.

Please address Trevor's comments. I came to see if I could help you a bit further but since you have not addressed Trevor's comments I see no point. This article needs a lot more development. Be sure to email me when you think that you have advanced this page.

There is a lot known about this topic. Read more and write more. Don't assign specific parts to different authors. Instead everyone read and every write every topic. You need the synergy that comes with multiple minds addressing a single topic. Content and polish really improves fast when you have this. 

Drug addiction has been characterized by an alteration in physical and mental state and especially desire/craving for drugs (Sinha, Rajita pg. 85) *1*. Drugs of abuse cause three types of epigenetic alteration in the brain. These are (1) histone acetylations and histone methylations, (2) DNA methylation at CpG sites, and (3) epigenetic downregulation or upregulation of microRNAs. <- This is highly misleading. You should (almost) never give the impression that there is only some small possible set of possibilities in biology. Just as an example, histone ubiquitylation is an additional epigenetic modification that could very reasonably be implicated in addiction. (See Epigenetics of cocaine addiction for some details.) <- You should be able to make a link.

Histone modification can alter chromatin structure by loosening or tightening the DNA, which is wrapped around a nucleosome, leaving DNA exposed for or protected from transcription inducing proteins like RNA polymerase.(Nestler pg.629)*1* Histone deacetylase, HDAC, allows for transcription to occur by giving slack to the DNA adhered to the nucleosome <- This is incorrect. HDACs *de*acetylate and make chromatin less accessible and shut off transcription (at least in the simple model we usually adhere to), allowing for proteins like FosB, which have been hypothesize to be crucial in addiction, to increase in production. The family of proteins called Fos, are comprised of FOS, FOSB, FOSL1, and FOSL2, and expressed transiently following acute exposure to drugs of addiction, but FosB is especially produced in the reward-related pathways of the striatum.(Bali pg.380) After chronic administration of drugs with abuse liability, FosB begins to be expressed with enduring effect and has incited important support for research into the long-lasting effects produced by FosB mediating relapse. (Nestler pg.634)*1*

This is a good start, but say more. Expand on the mechanism here. What happens epigenetically after acute exposure to drugs? How's this related to the reward pathways? Why specifically reward pathways? There's a lot to explain here that you don't get into.

Give a better account of the relationship between histone acetylation and transcriptional activation. Don't forget that histone acetylation can be reinforced by inducing the binding of other histone acetyltransferases, bromodomain-containing proteins, and other components of actively-transcribed euchromatin.

*1* Please convert all citations to proper Wikipedia formatted citations. Please review the Wiki instructions on this or look at someone else's Wiki to see how to do it (e.g. Epigenetics of Allergies by Sarah Tucker, Daniel Naves OR Epigenetics of Schizophrenia by Rhea Gogia, Ren Smith, Gunnar Gray. You could also contact someone in those groups to ask question if you need to). If you look at someone else's work in raw edit mode then please be super careful not to change anything.

Drug addiction has been characterized by an alteration in physical and mental state and especially desire/craving for drugs (Sinha, Rajita pg. 85). Depending on the drug of abuse, different types of epigenetic modification can be elicited in the brain, like histone acetylation or methylation, DNA methylation at CpG sites, and epigenetic downregulation or upregulation of microRNAs. Histone methylation is associated with transcriptional activation and repression while histone acetylation is correlated with the former, primarily. <- This is pretty confusing. Make this clearer.  When researching the epigenetic alterations that occur due to chronic exposure of ∆9-THC, tetrahydrocannabinol, histone acetylation and methylation have been prominent hallmarks shown in rats (Prini, Pamela pg. 8). Increases in histone acetylation, especially in the NAc, also known as the mesolimbic rewarding pathway, at H3K14, supports the hypothesis that NAc histone acetylation is correlated to addiction-related behaviors like place conditioning (Prini, Pamela pg. 8-9).

Histone acetylation states can alter chromatin structure by loosening or tightening the DNA, which is wrapped around a nucleosome, leaving DNA exposed for or protected from transcription inducing proteins like RNA polymerase (Nestler pg. 629). Histone deacetylase (HDAC) allows for transcription to occur by giving slack to the DNA adhered to the nucleosome, allowing for proteins like FosB, which have been hypothesized to be crucial in addiction, to increase in production. The family of proteins called Fos, are comprised of FOS, FOSB, FOSL1, and FOSL2, and expressed transiently following acute exposure to drugs of addiction, but FosB is especially produced in the reward-related pathways of the striatum.(Bali pg.380) After chronic administration of drugs with abuse liability, FosB begins to be expressed with enduring effect and has incited important support for research into the long-lasting effects produced by FosB mediating relapse. (Nestler pg.634)

Why is this duplicated?

What's the mechanism here? There's just almost nothing that's explained. Yes histone methylation and acetylation are affected, but so what? Also, be careful with jargon. Most readers probably won't know what the NAc is or why it's important here.

Opioid exposure, whether prolonged or given at higher doses, can have a significant influence on gene expression through several epigenetic modifications. Firstly, opioid use can affect the histones in which DNA is wound around, impacting its ability to be accessed and transcribed. There is a pattern of hyperacetylation of histone marks on the H3 proteins of histones, specifically on H3K27ac, located in the striatum; similarly, there is an increase in acetylation in certain marks of the H4 proteins in the nucleus accumbens (Browne pg. 23). This process of increased acetylation opens up the DNA to being transcribed more - therefore with increased or prolonged use, there will be neuroplasticity towards these behaviors, and predisposing one to addiction. Secondly, DNA methylation, which blocks gene transcription by preventing RNA polymerase II to bind to the DNA, <- Reality is much more complicated. There is recruitment of HDACs, HMTs, chromodomain proteins, etc. This is all important to note and include. is impacted by opioid use as well. The µ-opioid receptor gene (OPRM1) transcribes the molecular target of opioids. The promoter of this gene has a CpG island, and this region becomes hypermethylated not only with prolonged use of opioids, but at high doses as well (Sandoval-Sierra). Thirdly, opioid use affects enzymes and transcription factors involved in gene expression, therefore affecting the sequences and cascades that allow transcription to occur smoothly and uninterrupted. <- Are you implying that transcription elongation is affected by opioid use? What's the evidence for this? For example, the activity of histone deacetylase 5 (HDAC5), an enzyme that chemically alters histone tails, is downregulated, specifically in the NAc (Nielsen). This modification increased transcription at these target genes. <- What target genes? Similarly to increased acetylation, plasticity can be influenced by the effects of opioids on transcription factors. For example, the activator protein-1 (AP-1) mediates gene regulation and “promotes plasticity within reward regions,” and is responsible for the behavioral responses to cocaine specifically (Browne pg. 27).

What's the relationship (mechanism) between histone acetylation and neuroplasticity? You present this link as if it's obvious, but it's not.

What is the effect on transcription factors? Are they activated through post-translational modifications? Increased expression? What's really going on here?

~~General Comments~~

This article is really lacking. This absolutely does not meet what we're asking for in substantial contributions for a writing intensive course. I did a quick word count and found ~800 words, and this included the duplicate paragraph. Not only is this insubstantial, but it contains many basic factual inaccuracies and a very limited scope with respect to both the topics that you're covering and the epigenetic mechanisms you're taking into account. This really needs substantial revisions.

Some additional things to work on: clear up the writing. It's kind of flowery and indirect, and I think it's obscuring the points that you're making. There is some jargon throughout that needs to be clearly explained and given a full account of how it works into the mechanisms you're discussing. There needs to be much more mechanistic detail throughout the article. Finally, the references need to be correctly formatted.

Bali, Purva, and Paul J Kenny. “Transcriptional Mechanisms of Drug Addiction.” Dialogues in clinical neuroscience 21.4 (2019): 379–387. Web.

Browne CJ, Godino A, Salery M, Nestler EJ. Epigenetic Mechanisms of Opioid Addiction. Biol Psychiatry. 2020 Jan 1;87(1):22-33. doi: 10.1016/j.biopsych.2019.06.027. Epub 2019 Jul 8. PMID: 31477236; PMCID: PMC6898774.

Feng, J.; Nestler, E.J. Epigenetic mechanisms of drug addiction. Curr. Opin. Neurobiol. 2013, 23, 521–528

Murphy, Susan K et al. “Cannabinoid Exposure and Altered DNA Methylation in Rat and Human Sperm.” Epigenetics 13.12 (2018): 1208–1221. Web.

Nestler, Eric J. “Transcriptional mechanisms of drug addiction.” Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology vol. 10,3 (2012): 136-43. doi:10.9758/cpn.2012.10.3.136. Web.

Nielsen DA, Utrankar A, Reyes JA, Simons DD, Kosten TR. Epigenetics of drug abuse: predisposition or response. Pharmacogenomics. 2012 Jul;13(10):1149-60. doi: 10.2217/pgs.12.94. PMID: 22909205; PMCID: PMC3463407.

Prini, Pamela et al. “Chronic Δ9-THC Exposure Differently Affects Histone Modifications in the Adolescent and Adult Rat Brain.” International journal of molecular sciences 18.10 (2017): 2094–. Web.

Sandoval-Sierra JV, Salgado García FI, Brooks JH, Derefinko KJ, Mozhui K. Effect of short-term prescription opioids on DNA methylation of the OPRM1 promoter. Clin Epigenetics. 2020 Jun 3;12(1):76. doi: 10.1186/s13148-020-00868-8. PMID: 32493461; PMCID: PMC7268244.

Sinha, Rajita. “Modeling Stress and Drug Craving in the Laboratory: Implications for Addiction Treatment Development.” Addiction Biology, vol. 14, no. 1, Jan. 2009, pp. 84–98. EBSCOhost, https://doi.org/10.1111/j.1369-1600.2008.00134.x. Web.

Wang Y, Krishnan HR, Ghezzi A, Yin JCP, Atkinson NS (2007) Drug-induced epigenetic changes produce drug tolerance. PLoS Biol 5(10): e265. doi:10.1371/journal. pbio.0050265. Web.

Wong, Chloe C. Y, Jonathan Mill, and Cathy Fernandes. “Drugs and Addiction: An Introduction to Epigenetics.” Addiction (Abingdon, England) 106.3 (2011): 480–489. Web.