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Epigenetics, Epigenetic Inheritance, Heterochromatin Region, General…
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General Concept
Epigenetic inheritance describes the ability of different states, which may have different phenotypic consequences, to be inherited without any change in the sequence of DNA
Several different types of structures have the ability to sustain epigenetic effects:
:check: A covalent modification of DNA (methylation of a base)
:check: A proteinaceous structure that assembles on DNA
:check: A protein aggregate that controls the conformation of new subunits as they are synthesized
A gene methylated in its control region may fail to be transcribed, whereas an unmethylated version of the gene will be expressed
Replication of the methylated allele creates hemimethylated daughters that are restored to the methylated state by a constitutively active DNA methyltransferase (DNMT)
Their perpetuation depends on the ability of proteins in a heterochromatic region to remain bound to those regions after replication, and then to recruit more protein subunits to sustain the complex.
Usually the tails of histones H3 and H4 are not acetylated in constitutive heterochromatin. If heterochromatin becomes acetylated, though, silenced genes in the region may becomeactive. The effect may be perpetuated through mitosis and meiosis
When a gene is transferred, either by a chromosomal translocation or by transfection and integration, into a position adjacent to heterochromatin, it may become inactive as the result of its new location, implying that it has become heterochromatic
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HP1 (heterochromatin protein 1) is one of the most important Su(var) proteins
First the deacetylase acts to remove the modification at K14, and this allows the SUV39H1 methyltransferase (also known as KMT1A) to methylate H3K9 to create the methylated signal to which HP1 will bind.
Binding of HP1 to methylated histone H3 forms a trigger for silencing because additional molecules of HP1 aggregate along the methylated chromatin domain.
Formation of heterochromatin in the yeast S. pombe utilizes an RNAi-dependent pathway
The siRNA complex promotes methylation of histone H3K9 by the Clr4 methyltransferase (also known as KMT1, a homolog of Drosophila Su[Var]3–9). H3K9 methylation recruits the S. pombe homolog of HP1, Swi6
Heterochromatin formation at telomeres and silent mating-type loci in yeast relies on an overlapping set of genes known as silent information regulators (SIR genes)
Formation of heterochromatin is initiated when Rap1 binds to DNA. Sir3/4 bind to Rap1 and also to histones H3/H4. Sir2 deacetylates histones. The SIR complex polymerizes along chromatin and may connect telomeres to the nuclear matrix
This may inactivate the region, either because coating with the Sir3/Sir4 complex itself has an inhibitory effect, or because Sir2-dependent deacetylation represses transcription.
The Pc proteins function in large complexes. PRC1 (Polycomb repressive complex 1) contains Pc itself, several other Pc-Gproteins, and five general transcription factors
Pc itself has a chromodomain that binds to methylated H3, and E(z) is a methyltransferase that trimethylates histone H3K27.
In the absence of Pc-G proteins, these genes are initially repressed as usual, but later in development the repression is lost without Pc-G group functions
In contrast, Trithorax group (TrxG) proteins have the opposite effect of Pc-G proteins: They act to maintain genes in an active state
The TrxG proteins act by making chromatin continuously accessible to transcription factors. Although Pc-G and TrxG proteins promote opposite outcomes, they bind to the same PREs, which can regulate homeotic gene promoters some distance away from the PRE through looping of DNA.
Methylation of DNA occurs at specific sites. In bacteria, it is associated with identifying the bacterial restriction-methylationsystem used for phage defense and also with distinguishing replicated and nonreplicated DNA
Methylation in eukaryotes principally occurs at CpG islands in the 5' regions of some genes; these islands are defined by the presence of an increased density of the dinucleotid sequence CpG
Change in methylation status with aging, known as epigenetic drift, is thought to be a contributing factor to the increasing phenotypic variability that is observed with aging of monozygotic twins
UHRF1, that is important for the maintenance of methylation both locally and globally through its association with Dnmt1. This protein is able to recognize CpG dinucleotides and to preferentially bind to hemimethylated DNA
UHRF1 has dual functions in recognizing sites for maintenance methylation as well as in recruitment of the maintenance methyltransferase to these sites for methylation of the unmethylated CpG on the newly synthesized strand, thereby preserving methylation patterns with each cell replication
Strikingly, UHRF1 also interacts with methylated histone H3, which connects the maintenance of DNA methylation with the stabilization of heterochromatin structure.
Positive feedback loops contribute to the stability of epigenetic states.(H3K9 methylation, HP1 interaction with Dnmt1)
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:one: Loss of methylation at a site occur due to incomplete fidelity of Dnmt1 (passive demethylation)
:two: Block the maintenance methylase from acting on site when it is replicated, after a second replication cycle, one of the daughter duplexs will be unmethylated.
:three: Actively demethylate the site, either by removing methyl group diretcly from cytosine or by excising the methylated cytosine or cytidine from DNA replacement by a repair system.