Invest in ME Conference 12: First Class in Every Way
OverTheHills wraps up our series of articles on this year's 12th Invest in ME International Conference (IIMEC12) in London with some reflections on her experience as a patient attending the conference for the first time.
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Epigenetics for Dummies

Discussion in 'General ME/CFS Discussion' started by Kimsie, Jan 29, 2015.

  1. Kimsie

    Kimsie Senior Member

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    I have been learning a lot about this lately and I thought I would post what I have been learning and some of my thoughts about it. This first post is just an opener, because I am going to try to keep the information in smaller increments. I will add more later and maybe other people will want to add to it also, or correct me if I get something wrong, but let's try to keep it really simple and easy to understand.
    **************************************************
    I am marking the posts with post numbers so that new people can find the "seminar" posts easily by scanning.
    Post 1.jpg

    DNA is wrapped around histone, which is sort of like a bunch of scraps of thread rolled in a ball with a lot of tails hanging out.
    Histone DNA 1.jpg
    There is methyl and acetyl stuck on the tails. If there is more methyl on the tails the DNA pulls tighter and there is less gene expression. If there is more acetyl then the DNA is looser and there is more gene expression.
    methyl and acetyl.jpg

    Sirtuins, or sirt1 through sirt7, take acetyl off of the tails, so it causes less gene expression.

    LSD1 takes methyl off of the tails, so it causes more gene expression.
    LSD1 and sirt1.jpg
    If DNA is too tight it is overmethylated and has less expression.

    If DNA is too loose it is undermethylated and has more expression.

    In this sense, overmethylation and undermethylation have nothing to do with the methylation cycle, which produces SAMe.
     
    Last edited: Jan 29, 2015
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  2. Hanna

    Hanna Senior Member

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    That's a great idea Kimsie, thanks.
     
  3. drob31

    drob31 Senior Member

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    Thanks Kimsie, you're the best. :)
     
  4. Jonathan Edwards

    Jonathan Edwards Senior Member

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    Seriously cool seminar. I learnt a load of stuff I was too afraid to ask and too lazy to look up! And great pics.
     
  5. Kimsie

    Kimsie Senior Member

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    Thank you all for your comments. I wasn't even sure if anyone would be interested. I am trying to make it easy and fun to follow so that people don't have to waste precious energy trying to understand.
     
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  6. leela

    leela Slow But Hopeful

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    Much appreciated, @Kimsie. Keep 'em comin' if you can.:love::nerd:
     
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  7. barbc56

    barbc56 Senior Member

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    That's appreciated. Thanks!
     
  8. Kimsie

    Kimsie Senior Member

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    Post 2.jpg
    Extreme confusion reigns for people trying to understand epigenetics, because the end result of the action of sirtuins can be either increased or decreased enzyme activity.

    This is because sirtuins work on enzymes and transcriptional regulators and other things in addition to histones and they have different effects on different things.
    Various actions of sirtuins.jpg

    Because of this, some things are activated by sirtuins and others are inhibited.

    Instead of removing acetyl, some sirtuins break off part of the NAD+ molecule and put it on an enzyme.

    All sirtuins have to use NAD+ to function.

    NAD+ is used to transfer energy to the electron transport chain in the mitochondria to make ATP.

    NAD+ availability or the NAD+/NADH ratio is one of the most important factors controlling sirtuin activity.
     
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  9. Kimsie

    Kimsie Senior Member

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    Post 3.jpg
    What is NAD+.jpg
    NAD+ does other things, too. Too many things to mention here.

    The nucleus, cytosol and mitochondria each make their own NAD+.
     
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  10. ahmo

    ahmo Senior Member

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  11. eafw

    eafw Senior Member

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    Can you explain gene expression and why it is relevant ?
     
  12. Kimsie

    Kimsie Senior Member

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    Yes, PRPP is also used in the purine synthesis and recycling pathways.
     
  13. Kimsie

    Kimsie Senior Member

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    OK, thank you for the feedback. I'll work on a post about that.
     
  14. Kimsie

    Kimsie Senior Member

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    Post 4.jpg
    Every living thing has a set of instructions telling how each part of itself is made and when each part is made and what to do if something happens to interfere with normal functions. This set of instructions is contained in something called genes, and most genes are stored in a special place in the cell called the nucleus, where they are stuck together in the chromosomes, but a few genes are found in the mitochondria.

    Genes.jpg
    If all of these instructions were being carried out at once chaos would reign, so there are ways of controlling, or regulating, which instructions are being carried out at different times and how much they are being carried out.
    Gene instructions.jpg
    A gene has the instructions for making one protein. The protein has a special job in the body. How much, how little, and when the gene’s instructions are being used is called “genetic expression”.

    The instructions have to be copied in order to be used. Epigenetics refers to the process of making the instructions more or less available for copying. There are several other ways in which gene expression may be regulated after the instructions are copied, but I am not going to talk about them in this post.
     
    Last edited: Jan 30, 2015
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  15. ahmo

    ahmo Senior Member

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    Hi Kimsie. you are doing a great job! Thank you. Someone just posted the following on another thread. Scroll down the linked page for a diagram showing mito including sirtuins.

    ...then I saw that I had another tab with a sirtuin link. You really got me searching! And again it's in the context of reseveratrol. http://sirtuins.info/

     
    Last edited: Jan 30, 2015
  16. Kimsie

    Kimsie Senior Member

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    Post 5.jpg
    In the first post I said that taking methyl off of histones causes more gene expression. That’s perfectly true – some of the time.

    But sometimes it causes less gene expression because it works together with different proteins called effector proteins and whether the gene expression is increased or decreased depends on which effector protein is being targeted.

    Whew, that’s getting too technical. I think it is easier to look at specific areas which might be important to people with these illnesses rather than to try to understand all about how methylation affects histones.

    Today I want to talk about deiodinase genes, called DIO2 and DIO3.

    DIO2 activates the thyroid hormone by changing T4 to T3. This happens not only in the thyroid gland, but also in other parts of the body.

    DIO3 changes the thyroid hormone into an inactive form.

    The body uses DIO2 and DIO3 to regulate the amount of active thyroid available so that different amounts of thyroid can be used in different parts of the body.

    LSD1, which takes methyl off of histones, increases the activity of DIO2 and decreases the activity of DIO3. This means that it increases the activity of thyroid hormone in tissues.

    Sirt1 lowers the activity of DIO2 so it can lower thyroid activity in tissues.
    Thyroid.jpg
    LSD1 also interacts with FoxO3, a gene copying protein. DIO2 has less activity without FOXO3. We will learn more about the FOX proteins in later posts.

    So LSD1, sirt1 and FOX are all involved in controlling the amount of active thyroid in various parts of the body. There are some other things which help control it, too.
    Mulling it over.jpg
    LSD1 requires folate so perhaps sometimes the increase in energy from taking folate might be from an increase in active thyroid due to an increase in LSD1 activity. Another possibility is that the increased folate allows for more purine synthesis to make NAD and ATP.

    DIO2 activity in most tissues of people with CFS may be lower. What is causing this?
    Technical Stuff.jpg
    This part has links to references. This is for the techie types.

    “Rather, the effect of histone methylation impacts on the transcriptional activity of the underlying DNA by acting as a recognition template for effector proteins modifying the chromatin environment and leading to either repression or activation. Thus, histone methylation can be associated with either activation or repression of transcription depending on which effector protein is being recruited.”


    Here, we report that the histone H3 demethylating enzyme (LSD-1) is essential for transcriptional induction of D2 and repression of D3.

    Furthermore, endogenous LSD-1 interacts with FoxO3a, and abrogation of FoxO3-DNA binding compromises the ability of LSD-1 to induce D2.

    Additionally, D2 also has an opposite response from that of D1 to physiologic and emotional stress, depression, both dieting and weight gain, PMS, diabetes, leptin resistance, chronic fatigue syndrome, fibromyalgia, inflammation, autoimmune disease, and systemic illness. D2 is stimulated and up-regulated (increased activity) in response to such conditions, increasing intra-pituitary T4 to T3 conversion while the rest of body suffers from diminished levels of active T3. This causes the TSH to remain normal despite the fact that there is significant cellular hypothyroidism present in the rest of the body.

    SIRT1 het mice (i.e. lower SIRT1 expression) had elevated expression of Dio2,
     
    Last edited: Feb 2, 2015
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  17. samanthawaters

    samanthawaters

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    I would love to know more about LSD-1 if possible :)

    Samantha
     
  18. wastwater

    wastwater Senior Member

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    I would like to hear more about FOX proteins please
     
  19. erin

    erin Senior Member

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    @Kimsie thank you so much for this.
     

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