User:Kelsidc/Main Sandbox

Epigenetics of Autism--People playing in this sandbox are: Kelsi Cox, Valentina, Ria, Christina

Trevor's comments in magenta

Article Evaluation/summary of proposed changes:

• C class article of mid importance.
• Very little activity in the talk page, which is surprising, because this article is within the scope of several WikiProjects (it was created by a UT class with WikiEducation and is in the scope of WikiProject Autism).
• This article is relevant; there are several hundred review articles matching the search criteria for this topic on PubMed, so there's a sufficiently large body of research to support this article.
• This article is FAR too technical. There should be a broader overview of why the topic is important and why it's being researched.

• • The sections of this article need to be more clearly organized. The authors jumped into very technical discussions of the relevant research, without providing solid context and organization for each of these discussions. Also, there are too many technical tables in each of the sections, which make the article visually unappealing, difficult to grasp, and overly complicated. The tables should be removed, at least at the beginning of a new draft, and each of the sections should be reformatted with the explicit aim of providing basic context of their relevance, with many review articles for support.
  • The Lead needs a clearer definition of "epigenetics of autism." The lead starts with a discussion of Autism Spectrum Disorder, which is helpful because a definition of "autism" should be given first. However, I think it might be more helpful to define "epigenetics" first, then to give a broad overview of autism that links to relevant Wiki articles, and finally to focus on a broader picture of the application of epigenetics to autism.

• • • I think this order makes more sense because most readers will likely be familiar with ASD, but many will not be familiar with epigenetics, so it's better to start with the lesser-known terms in the Lead. That way, readers can quickly understand what the article is about rather than waiting for the third paragraph of the Lead.

• • • • Also, because links to articles generally contain snippets of the leads of those articles, having the best lead possible could increase the number of links to this article.

• • • It's been suggested that epigenetics of autism should be made a subsection of the article on autism, rather than being a separate article. Merging the two in this way could be helpful, but given how large the body of research is on this topic, I lean towards keeping the two articles separate. HOWEVER, this poses a slight difficulty, because the Lead of the epigenetics article provides inadequate context on the nature of autism and its relation to epigenetics. But that could be resolved by linking to the autism article, as I suggested above, provided that at least a few sentences of brief overview/summary is provided in this article, as well.

Fair point. Sounds good to me.

• This article needs fewer primary sources and more review/secondary sources.
• This references section of this article needs to be reformatted.

Add to the "The Link to Rett Syndrome" section of Epigenetics of Autism.

- MeCP2 regulates mRNA splicing through 5hmc (is oxidized by TET enzymes from 5mc to 5hmc; needed for DNA demethylation; stable epigenetic mark) and changes in histone markers. 5hmc impairs binding of MeCP2. This leads to effects in synaptic plasticity and mRNA splicing. Somehow this explains the mis regulation of Serine/Arginine Repetitive Matrix 4 nSr100 - dependent splicing in over 1/3 of autistic brains. To add, Mecp2 binds more to Reelin (RELN), glutamate decarboxylase 1 and 2 (GAD1 and GAD2) in autistic brains which leads to lower expression of RELN and GAD1 mRNA.

Include research on Folate-methionine?

It wouldn't hurt to develop this a bit in a draft and see if it fits.

What is your citation for this? Add citations in the recommended Wiki way so that we can figure out the citations. I think your WikiEdu course went through this. Other students have figured this out and you can look at any real Wiki page to learn how this is done. Or you can use the cite button.

Histone deacetylases (HDACs) and ASD

• The strongest link of HDACs to ASD has been found in prenatal HDAC inhibition research. Valproic acid (VPA) is a weak HDAC inhibitor that has been shown to increase the risk of ASD in pregnant moms that use it. Valproic acid is an anticonvulsant (used to treat seizures/ epilepsy). In mice studies, prenatal exposure to trichostatin A (TSA) and VPA (both are HDAC inhibitors) lead to ASD symptoms. To add, mRNA levels of Nlgn1, Shank2, Shank3, and Cntnap2 (genes related to synaptogenesis) were changed from TSA inhibition. These genes are linked to ASD as well.
• HDAC inhibitors (VPA and TSA) in prenatal mice models increase histone acetylation and decrease HDAC expression. Decreases social interactions / behavior observed in mice, rats, voles and non human primates exposed to VPA prenatally on E12.5 (embryonic day). Decreases social behavior primarily observed in males and sometimes females displayed no social deficits. Exposures on different embryonic days had not results in social deficits/ decreased social behavior in adolescents rodents. Long term effects of HDAC inhibition may differ from immediate effects,
• Post natal HDAC inhibition has the opposing effects. ASD symptoms can be improved. Romidepsin and MS-275 (HDAC inhibitors) improves social behaviors (preference and interaction time) in Shank3- deficient mice. TSA increases histone acetylation at the oxytocin and vasopressin receptors of the nucleus accumbens (NA) in female voles (like pair bonding). Beta hydroxybutyrate (a product of the ketogenic diet and inhibitor of class 1 HDAC) has shown to improve social behavior/skills in children (small clinical trials).

Lots of good info in this section, but consider thinking about how to turn this into a consistent statement/argument/thesis. You have a big collection of facts about HDACs and ASD - now what does this mean overall? How do you summarize the role of HDACs in ASD, and what does this say about levels of histone acetylation and ASD?

Should we include the similar epigenetics between other psychiatric disorders and ASD?

This could be worth a brief mention in passing, but I don't think it's worth spending too much time expanding on this. It seems pretty extraneous.

This is your best section but even so it is sort of a paraphrase of what is in one review. It is a good start. But you must clear the starting point now. You must read way more. There are three of you. A lot can be learned if you all really work on reading the literature, get together an discuss it. Don't work on stuff by yourself. You have a better chance of understanding if you have real discussions about it and then write. Time to turn it up a couple of notches.

Just want to make a mention of the idea that many mental illnesses are thought to contain a common base which sort of promotes instability. Then other things are overlayed which specifies exactly which type of illness one has. I don't know of a paper that says this as explicitly as I have but the data and discussion in the following paper strongly leads one to this conclusion. An atlas of genetic correlations across human diseases and traits. Brendan Bulik-Sullivan et al. Nature Genetics 2015 v47. This is not an epigenetics paper but a GWAS paper (identifies genes likely involved). Figure 2 shows you that diseases like Schizophrenia, Bipolar disorder and Depression seem to be related. Autism does not seem to be related to anything here but the fact that other mental illnesses do show interrelationships makes it likely that autism does as well. Of course, you need to find established experts pointing out similarities, you cannot do it yourself because this is not a research article but instead an encyclopedia article. This is a very long way around of me saying that it is worth a bit of hunting.

Also, unless something has changed recently then Rett Syndrome is a reasonable place to look for genes that can produce autistic-like behavior.

Potential review articles:

Genetics and epigenetics of autism: A Review.

Implication de l’épigénétique dans les troubles du spectre autistique : revue de la littérature [Epigenetics' implication in autism spectrum disorders: A review]

Epigenetics and autism.

Epigenetics of Autism Spectrum Disorder: Histone Deacetylases

The Promise of DNA Methylation in Understanding Multigenerational Factors in Autism Spectrum Disorders (Source?

This is a good start, but I get the feeling that there is a lot more you can add here. I think you allude to a lot of this in your top summary section, but this was a little unspecific so that I'm not sure what exactly you're planning to change in a lot of these sections - that is, I know what you're planning to change or improve but not necessarily how you plan to do so. I recommend putting a lot of work into your first draft so that I can give more specific comments/suggestions on it.

For some of my more general comments, I have no clue why this article is mostly divided up into chromosomes. I think it makes much more sense to break this up into a discussion of how epigenetic mechanisms cause autism. Moreover, I think the article does a poor job of explaining the role of which a lot of these genes/modifications are related to autism, e.g. what is causal? What are the mechanisms at play here? How does what is discussed in the article cause or contribute to autism? I think it's similar to the comment I made under one of the sections above - there seems to be a list of a lot of facts, but little explanation of what's going on. To me, these seem to be two of the largest improvements that need to be made to the article. A lot of this may be somewhat speculative at this point (as ASD is incredibly complex), but use the most recent reviews to guide what current opinion is in the field.

Outline of Article

Lead:

• good Definition of autism and autism spectrum disorder
• good definition of epigenetics
• What are the general ways that epigenetics has been applied to autism?

Epigenetic Causes of ASD [or "Autism"?]

15q11-13 duplication

In humans, chromosome 15q11-13 is the location of a number of mutations that have been associated with Autism spectrum disorders (ASD).

Duplications of 15q11-13 are associated with about 5% of patients with ASD and about 1% of patients diagnosed with classical Autism. 15q11-13 in humans contains a cluster of genetically imprinted genes important for normal neurodevelopment. (Table 1) Like other genetically imprinted genes, the parent of origin determines the phenotypes associated with 15q11-13 duplications. "Parent of origin effects" cause gene expression to occur only from one of the two copies of alleles that individuals receive from their parents. (For example, MKRN3 shows a parent of origin effect and is paternally imprinted. This means that only the MKRN3 allele received from the paternal side will be expressed.) Genes that are deficient in paternal or maternal 15q11-13 alleles result in Prader-Willi or Angelman syndromes, respectively, and duplications in the maternal copy lead to a distinct condition that often includes autism. Overexpression of maternally imprinted genes is predicted to cause autism, which focuses attention to the maternally expressed genes on 15q11-13, although it is still possible that alterations in the expression of both imprinted and bilallelically expressed genes contribute to these disorders. The commonly duplicated region of chromosome 15 also includes paternally imprinted genes that can be considered candidates for ASD.

Genes on 15q11-13 can be classified into three main categories:

• GABA_A receptor genes:

Members of the GABA receptor family, especially GABRB3, are attractive candidate genes for Autism because of their function in the nervous system. Gabrb3 null mice exhibit behaviors consistent with autism and multiple genetic studies have found significant evidence for association. Furthermore, a significant decrease in abundance of GABRB3 has been reported in the brain of AS, AUT and RTT patients. Other GABA receptors residing on different chromosomes have also been associated with autism (e.g. GABRA4 and GABRB1 on chromosome 4p).

• Maternally imprinted genes:

There are two maternally imprinted genes in 15q11-13, UBE3A and ATP10A (Table 1) and both lie toward the centromeric end. Both these genes are important candidates for ASD. Significant decrease in UBE3A abundance has been observed in post mortem brain samples from patients with AUT, AS and RT. Patients with autism have also shown abnormalities in methylation of the UBE3A CpG island.

• Paternally imprinted genes:

Most of the genes in 15q11-13 are paternally expressed. Gene expression analysis of paternally expressed imprinted genes has revealed that, in some cases excess of maternal 15q11-13 dosage can cause abnormal gene expression of the paternally expressed genes as well (even though the paternal 15q11-13 is normal).

Regulation of gene expression in 15q11-13:

Regulation of gene expression in the 15q11-13 is rather complex and involves a variety of mechanisms such as DNA methylation, non-coding and anti-sense RNA.

The imprinted genes of 15q11-13 are under the control of a common regulatory sequence, the imprinting control region (ICR). The ICR is a differentially methylated CpG island at the 5′ end of SNRPN. It is heavily methylated on the silent maternal allele and unmethylated on the active paternal allele.

MeCP2, which is a candidate gene for Rett syndrome, has been shown to affect regulation of expression in 15q11-13. Altered (decreased) expression of UBE3A and GABRB3 is observed in MeCP2 deficient mice and ASD patients. This effect seems to happen without MeCP2 directly binding to the promoters of UBE3A and GABRB3. (Mechanism unknown) However, chromatin immunoprecipitation and bisulfite sequencing have demonstrated that MeCP2 binds to methylated CpG sites within GABRB3 and the promoter of SNRPN/SNURF.

Furthermore, homologous 15q11-13 pairing in neurons that is disrupted in RTT and autism patients, has been shown to depend on MeCP2. Combined, these data suggest a role for MeCP2 in the regulation of imprinted and biallelic genes in 15q11-13. However, evidently it does not play a role in the maintenance of imprinting. Talk to me Monday at office hours if you don't understand how to do this.

I don't get it. You have lots of text copied form original article but what are you planning to do with it. I don't see any changes.

In the paper Marballi and MacDonald. 2021. Proteomic and transcriptional changes associated with MeCP2 dysfunction reveal nodes for therapeutic intervention in Rett syndrome. Neurochemistry International vol 148 They say the following: "Mutations in epigenetic regulators often lead to neurodevelopmental or neuropsychiatric disorders (Fahrner and Bjornsson, 2019; Zoghbi and Beaudet, 2016) and disruptions in epigenetic regulators, particularly chromatin modifiers, are disproportionately identified in studies of autism spectrum disorders (De Rubeis et al., 2014; Iwase et al., 2017; Zoghbi and Beaudet, 2016)."

They also say " An increase in levels of peripheral proinflammatory markers is often associated with neurodevelopmental disorders such as autism (Siniscalco et al., 2018), schizophrenia (Khandaker et al., 2015) and RTT (Pecorelli et al., 2020)."

Now none of this is directly useful but this is how I often find stuff on new topics. I find connections like this, then look at the cited papers (in this case to see if they have epigenetic mentions, then I look for modern papers (1 or 2 y old) that cite these papers and see if these make any useful connections.

Another way to find things is to search for the keyword autism and an enzyme (HDAC, HAT, remodeler, methylase, do everything). This works because sometimes papers are so highly focused that they mention the enzyme but not the word epigenetics.