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Lecture 6

Lecture 6

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Biology (Sci)
BIOL 300
Siegfried Hekimi

th BIOL 300 September 19 2012 Lecture 6 Dr. Hekimi We have seen so far the bottom half of this diagram, i.e. what is necessary once a gene is accessible for transcription to occur  This includes RNA Polymerase, all of the necessary general TFs, as well as gene- specific TFs and the Mediator complex There are a number of conditions which need to be met before the DNA is accessible to be transcribed efficiently  Chromatin can either be in a packed conformation or in a loose conformation; this is regulated by repressors, which compress chromatin, and activators, which de-compress the DNA  In vitro tests have been shown using purified DNA to show binding sites for some of these activators and repressors o You can measure the efficiency of how well these activators and repressors work, we have seen de-compression up to 10,000 fold by certain activators (i.e. a very strong activator)  This will then lead to a change in gene expression  Because it’s so difficult to access DNA, cooperative binding becomes important; the more activators that are bound, the looser the DNA will be and the higher the level of gene expression o The same is true for repressors The nucleosome is a tightly bound structure  Conformational changes don’t occur very easily because of its structure, allowing nucleosomes to bind and tighten DNA  They have a core region which binds and wraps DNA  They also have N and C terminal tails which do not directly bind to wrap the DNA o These tails are very flexible; X-ray diffraction has shown that not every histone has these tails on the same position (the tails appear blurry because the X rays never bounce off the same place) The residues at the N terminal regions of each histone and the C terminal regions of histones H2A and H3B are called histone tails  H3 and H4 have short, unmodified, C terminal tails which do not strongly affect gene expression  Histone N terminal tails are better conserved that the rest of the molecule which suggests a highly conserved function  Histone tails are rich in positive lysine residues o This allows potential for binding to the negative phosphate backbone of DNA (like linker DNA) 1 th BIOL 300 September 19 2012 Lecture 6 Dr. Hekimi  Removing these tails prevents chromatin compaction (in vitro and in vivo) o Shows how histone tails are involved in chromatin condensation in some way  Chromatin will interact with ATP-dependant remodelling complexes which can have multiple functions o E.g. push nucleosomes aside, modify DNA, etc.  Histones can also interact with enzymes that will modify their tails o These modifications can be covalent which have direct or indirect consequences such as  Interaction of other complexes such as DNA activators and repressors  Gene expression o The specific modifications of a sequence of DNA is known as the histone code  Remember a single histone has many tails, and it’s the combinatorial effects of all the modifications on all the tails which will ultimately decide how the chromatin will be affected o Each histone is made of 8 subunits, which can also be modified We can see a few of these modifications:  We don’t need to memorize the exact residues that are acted upon  Not every histone tail will have all of the modifications; the histone code represents a pattern of which histones have which modifications (there are many, many different possible combinations) o Epigenetic inheritance involves the transfer of non-genetic material from a parent cell to a daughter cell; an example of this is transmittance of the histone code from generation to generation  Some modifications include: o Histone acetyltransferase  E.g. H4 from above has 4 different acetylation points; the probability of acetylation depends on the number of time the histone has been associated with chromatin, which is a long-term mechanism of control over gene expression o Histone deacetylases  These will remove the acetyl group from lysines o Histone methyltransferase  Methylation of lysines will add bulk, tightening DNA, as well as prevent acetylation  Arginine methylation is PERMANENT as there are no arginine demethylases o Lysine demethylase  These will remove the methyl group allowing for acetylation o Kinases (phosphorylation)  Phosphorylation on a serine will add a big negative charge to a previously neutral molecule which affects DNA binding o Phosphatases 2 th BIOL 300 September 19 2012 Lecture 6 Dr. Hekimi  These will dephosphorylate histone tails removing the negative charge o Ubiquitination can happen on certain residues which can target the molecule for certain things (including protein degradation)  Ubiquitin is a small peptide which can be attached to certain molecules for signalling purposes Covalent modification of histone N terminal tails:  Acetylation is reversible o Occurs at specific lysine resides (not random); their location is important for the histone code o Neutralizes the positive charge on the lysine
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