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Lecture 7

Lecture 7

5 Pages
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Department
Biology (Sci)
Course Code
BIOL 300
Professor
Siegfried Hekimi

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st BIOL 300 September 21 2012 Lecture 7 Dr. Hekimi Functions of histone modifications:  Establishment of global chromatin environments o Chromatin is not the same everywhere in the chromosome: heterochromatin is silent while euchromatin is active o This requires establishing boundary elements to separate the types of chromatin  These are elements which prevents a particular state of chromatin to spread to regions where they don’t belong  Chromatin states are able to spread to different regions through specific mechanisms o Telomere centromere function:  Chromatin is packed here in particular ways in order to provide unique mechanical properties (e.g. pulling apart in anaphase by linking to nuclear envelope proteins)  Orchestrations of DNA based biological tasks o Regulation of gene expression in euchromatin o Requires delivery of chromatin modifying enzymes by DNA bound transcription factors Effects of histone tail modifications:  Reduction of the positive charge on these tails by acetylation and phosphorylation reduce their interaction with negatively charged DNA and decrease chromatin condensation (opens up structure) o We can see through the same way that removing the tails (in vitro) can also decrease chromatin condensation  Specific modifications may serve as new binding sites for proteins which can alter chromatin structure and function o I.e. the modifications create a “histone code” read by interacting proteins o These proteins can be recruited for different tasks, which can, for example, promoter Pol II binding or prevent it  N-terminal acetylation is clearly involved in the regulation of gene expression There are two protein domains which specifically interact with covalently modified histones, each with their own specific recognition site:  The bromodomain is found in several euchromatin associated proteins such as TFIID (TBP plus some other subunits with other functions including chromatin condensation) o Recognizes acetylated lysine residues  The chromodomain is found in several heterochromatin-associated proteins o It recognizes methylated lysine residues Examples of the histone code in actions:  Lysines 4 and 9 (K4&K9) of the H3 N-terminal tail can each be methylated o Methyl K4 is mostly found in euchromatin while methyl K9 is mostly found in heterochromatin o Binding of the protein HP1 to methyl K9 via its chromodomain initiates heterochromatin formation (compacts chromatin) 1 st BIOL 300 September 21 2012 Lecture 7 Dr. Hekimi  This can be done by physically tightening DNA or recruiting more methylases to the chromatin o Methylation of K4 or acetylation of K9 will inhibit chromatin formation by antagonizing the actions of HP1 The following diagram displays the modifications we talked about before (note, although both processes are happening on the diagram at the same time, this is not actually possible as they antagonize one another):  Binding of HP1 to Methyl K9 initiates heterochromatin formation through recruiting more HP1 and other mechanisms  The histone methyltransferase that acts on K4, called histone- 3-lysine-4 histone- methyltransferase (or H3K4 HMT) made by the gene Set9, acts to favor euchromatin formation because it blocks activity of various other proteins from coming in to condense the chromatin o Specifically, it blocks the entrance of nuclear remodelling complex NuRD, which could deacetylate K9, thus favoring K9 methylation  Similarly, acetylation of K9 will prevent entrance of H3K9 HMT, made by gene SUV39, which will methylate K9, thus favoring euchromatin formation o It will also block binding of HP1 which prevents heterochromatin formation  Clr3 is a histone deacetylase, which removes acetylation, can act on K14 and thus favor K9 methylation o Once again, HDAC Clr2 can somewhat block the actions of the H3K9 HMT SUV39 thus preventing heterochromatin formation  Thus there is an equilibrium which can be formed through the balanced actions of these processes The histone code contains many patterns of histone tail modifications, each pattern meaning a specific state of the chromatin:  We can see some of these states on the top of this diagram: o Each histone tails have modification sites, not all of them are modified at the 2 st BIOL 300 September 21 2012 Lecture 7 Dr. Hekimi same time; the combinations of modifications lead to the ultimate chromatin state  The lower part of this diagram shows the histone code itself; note that some of them are not known, denoted by the ?. o E.g. the first example, H3 with no modifications could possible mean gene silencing, while in the second example, acetylation of H3 K14 leads to gene expression (by the mechanism discussed above) Not only are all histone tails capable of being modified, there are many modifications and combinations of modifications on many different residues  There are over 60 different residues on histones where modifications have been detected either by specific antibodies or mass spectrometry  Another type of modification is sumoylation, which is similar to ubiquitination (it can be reversible or irreversible depending on the type)  Switching or removal/addition of amino acids is also another form of modification which can be recognized by various proteins Chromatin immunoprecipitation h
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