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DNA and chromatin regulation

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Created by Tracy Kim Kovach.

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  • leaf green style avatar for user AAXHG
    how does adding an acetyl group (Histone Acetyltransferase) lead to uncoiling/more transcription and how does removing an acetyl group (Histone Deacetylase) lead to condensation/less transcription?
    (12 votes)
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    • male robot hal style avatar for user Devin Young
      You have to know two things:
      1. DNA has negatively charged phosphate groups (anions)
      2. If histones are deacetylated, they are positively charged (cations).

      If you have a positive and negative charge together, they will be drawn to one another and increase density. If you acetylate the histone and make it non-polar, this attraction will no longer occur.
      (2 votes)
  • piceratops sapling style avatar for user Ryan Andrew Lindsey
    Around , she is describing the action of MBD's and I understand that they bind to methylated DNA sequences, but she lists a group of actions that didn't really make sense together.

    "Now, MBD proteins can recruit additional proteins to the locus, or particular location in a chromosome, certain genes, such as histone deacetylases and other chromatin remodeling proteins and this modifies the histones, forming condensed, inactive heterochromatin that is transcriptionally silent."

    What certain genes? Is that not supposed to be there? Do MBDs recruit HDATs and other remodeling proteins that inactivate the heterochromatin? A little clarification please.
    (5 votes)
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    • piceratops ultimate style avatar for user Marina Kudrow
      Any gene in the vicinity of highly methylated CpG islands is likely to be silenced. Silencing typically occurs by turning the euchromatin (DNA loosely wound around histones and thus accessible to DNA Polymerase binding) into heterochromatin (DNA densely packed around histones inacessible to DNA Polymerase). This is a multistep process.
      1. Methyl-binding domain proteins bind the methylated CpG islands in euchromatin.
      2. MBD's recruit the other proteins required to silence the gene. They act kind of like a multi-plug adapter does for an electrical outlet, allowing several proteins to bind one gene at the same time.
      3. The proteins required to turn euchromatin into heterochromatin are called chromatin remodelling proteins. For example, histone deacetylase, which removes any acetyl groups that might have been on the DNA (which would have kept it in an 'open' state)

      This can happen to any gene although usually the genes that are turned off are the ones that that type of cell will not need. For example, in a heart muscle cell, the genes for making axons (found in nerves) will be turned off.
      (11 votes)
  • spunky sam blue style avatar for user abhigyan
    what are MBDs?please explain.
    (3 votes)
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    • winston default style avatar for user Kenan
      As stated in the video, MBDs are Methyl CpG Binding Domain proteins. These are the proteins that bind to and facilitate methylation at CG rich regions in the DNA that are called CpG islands.
      (14 votes)
  • blobby green style avatar for user Daven Tai
    @. CpG sites occur on the same strand of DNA, and is not a reference to complementary C-G pairs on differents strands of DNA. A CpG island is defined as a segment of DNA that has an above average number of CG sequences. Also, DNA methylation is reversible as far as I know (http://www.ncbi.nlm.nih.gov/pubmed/24067648 is one of many papers that show that). Do you have a reference that says terminally differentiated cells cannot alter DNA methylation?
    (5 votes)
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  • blobby green style avatar for user bergloff
    Why is it important to silence CG rich regions in DNA? What problems does this cause?
    (3 votes)
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    • primosaur seedling style avatar for user sofimckenzie
      A methylated cytosine can be deaminated to change it to thymine (deamination can happen spontaneously in cells). This change of a whole base is not recognized by the DNA repair system, so the problem caused is a point mutation. This is why we have evolved to have very few CG sequences outside of the CpG "islands" which are usually in the very actively transcribed (and therefore unlikely to ever be methylated) areas around housekeeping genes (the default ON genes for the cell).
      (5 votes)
  • female robot grace style avatar for user OpenMinded737
    the ending was a bit confusing. Does that mean that heterochromatin can't form without MBD or does that mean that the newly formed heterochromatin is a more permanent and silent version of a heterochromatin
    (3 votes)
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  • mr pink red style avatar for user Karen
    How does epigenetic modifications affect variation in appearance and health?
    (2 votes)
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    • primosaur ultimate style avatar for user sjeanninehs
      Epigenetic is basically a changes of a gene expression through anything but altering its DNA sequence, so no insertion, deletion or change of nucleotides.

      The most extensively studied kind of epigenetics is DNA methylation, which may affect the activity of a promoter. In areas of a DNA rich in CG repeats (i.e. CpG islands), cytosines may be methylated or an addition of a methyl group, allowing proteins involved in gene repression to recognize it. Or the change itself may inhibit the binding of transcription factor(s) to DNA. It's a dynamic process in which each differentiated cells may develop its own unique methylation patterns, diversifying gene expression profiles, ergo causing the variation in appearance. If negatively regulated, it can cause the manifestation of certain diseases.
      (source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521964/)

      Another kind of epigenetic modification is chromatin remodeling, affecting the access of DNA for transcription proteins, therefore an expression of a gene.
      (0 votes)
  • blobby green style avatar for user Gurpal Sivia
    What are nucleosomes? And histone proteins..
    (1 vote)
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    • female robot grace style avatar for user tyersome
      Nucleosomes are made up of eight histones, which are a group of related proteins found in eukaryotes.

      Nucleosomes are an important component of the chromatin (the material that chromosomes are made of). Nucleosomes help to organize, compact, and regulate the DNA.

      This is also discussed in this video starting around

      Does that help?
      (2 votes)
  • leafers ultimate style avatar for user ff142
    Near the end when she said "certain genes such as histone deacetylases and other chromatin remodelling proteins" she meant "certain proteins", right?
    (1 vote)
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  • piceratops tree style avatar for user Amy S
    I read that lysines can get acetylated and arginines cannot - why is this?
    (1 vote)
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Video transcript

So, the regulation of gene expression can be modulated at virtually any step in the process, from the initiation of transcription all the way to post-translational modification of a protein, and every step in between. And it's the ability to regulate all these different steps that helps the cell to have the versatility and the adaptability of an efficient ninja, so that it expends energy to express the appropriate proteins only when needed. Or, you can think of the cell as a lazy couch potato that wants to expend the least amount of energy as possible. So, starting at the beginning of gene expression, let's talk about gene regulation as it pertains to DNA and chromatin regulation. Let's talk about the structure of DNA. DNA is packed into chromosomes in the form of chromatin, also know as supercoiled DNA. And so, chromatin is made up of DNA, histone proteins, and non-histone proteins. And there are repeating units in chromatin, called nucleosomes, which are made up of 146 base pairs of double helical DNA that is wrapped around a core of eight histones. And there are four different types of histones within this structure of eight that you should be aware of. And they're named H2A, H2B, H3, and H4, that's just the nomenclature they've been given. Now, acetylation occurs at the amino terminal tails of these histone proteins by an enzyme called histone acetyltransferase, which I'll just abbreviate as HAT. And this is a reversible modification, so the acetylation of histones is sort of kept in balance by another enzyme that removes these acetyl groups, which is called histone deacetylase, or HDAC. The acetylation of histones leads to uncoiling of this chromatin structure, and this allows it be accessed by transcriptional machinery for the expression of genes. On the flip side of this, histone deacetylation leads to a condensed, or closed structure of the chromatin, and less transcription of those genes. When these modifications that regulate gene expression are inheritable, they are referred to as epigenetic regulation. So, when it comes to gene expression and DNA, you can basically think of DNA as coming in two flavors, densely packed, and transcriptionally inactive DNA, which is called heterochromatin, and then less dense, transcriptionally active DNA, which is euchromatin. And I like to think of heterochromatin as being densely packed and hibernating, like heterochromatin and hibernating both begin with H, kind of like a bunch of densely packed bears that are closed off in their cave for the winter, whereas euchromatin is waiting there with open arms, welcoming the transcriptional machinery to transcribe away. Now often you will see that histone deacetylation is combined with another type of DNA regulatory mechanism, and that is DNA methylation, and this occurs in a process called gene silencing. And this is a more permanent method of sort of down-regulating the transcription of genes. And DNA methylation involves the addition of a methyl group, which is a carbon with three hydrogens, to the cytosine, DNA nucleotides, by an enzyme appropriately called methyltransferase. And this typically occurs in cytosine-rich sequences called CpG islands. Don't forget that cytosine pairs with g, guanine, so that's why they're cg islands that you'll find. DNA methylation stably alters the expression of genes, and so it occurs as cells divide and differentiate from embryonic stem cells into specific tissues. And so this is essential for normal development, and is associated with other processes, such as genomic imprinting, and x-chromosome inactivation, topics for another discussion. And abnormal DNA methylation has been implicated in carcinogenesis, or the development of cancer, so you can see how the normal functioning of DNA methylation is a critical regulatory mechanism for our cells. Now, DNA methylation may effect the transcription of genes in two ways. First, the methylation of DNA itself may physically impede the binding of transcriptional proteins to the gene. And second, and likely more important, methylated DNA may be bound by proteins known as methyl cpg-binding domain proteins, or MBDs, for short. Now MBD proteins can then recruit additional proteins to the locus, or particular location in a chromosome, certain genes, such as histone deacetylases, and other chromatin remodeling proteins, and this modifies the histones, forming condensed, inactive heterochromatin that is basically transcriptionally silent.