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<h2>Definition : Heritable changes in gene activity and expression that occur without alteration in DNA sequence</h2>
<hr h2>Different cells control switching on and off in different genes</h2>
<h2>Two well-known epigenetic modifications</h2>
<olul> <li> <h3>Chemical modification to the cytosine residues of DNA (DNA methylation)</h3> </li></ul> <p>DNA methylation usually occurs in cytosine followed by guanine (CpG) by DNA methyltransferase</p> <p>Most CpG motifs (Repetitive short pattern in DNA sequence or Protein sequence) are located near promoter regions.<sup>1)</sup></p> <p>Promoter is a region of DNA that initiates transcription of a particular gene</p> <p>The region that has lots of CpG motifs is called CpG island.</p> <p>Among around 60% of protein-encoding DNA sequences, their promoters are located in CpG islands.</p> <p>When a gene is activated, the methylation level of a nearby CpG island is low.</p> <p>When the gene switches off, the methylation level of the nearby CpG island is high.</p> <p>MeCP2(Methyl CpG binding protein 2) - acts as a decoder. It only binds to the methylated CpG islands<sup>2)</sup> and recruits other 'switching off' proteins<sup>3)</sup>.</p> <p>As a result, DNA is tightly packed and transcription factors cannot access to the promoter region</p> <p>The methylation pattern is inherited to the daughter cells</p> <p><img src="http://www.ks.uiuc.edu/Research/methylation/dna_mdna.png" />(http://www.ks.uiuc.edu/Research/methylation/dna_mdna.png)</p> <p><img src="https://www.elitenetzwerk.bayern.de/uploads/tx_templavoila/Forschungsbericht_Epicombing_Zillner_figure1.jpg" />(https://www.elitenetzwerk.bayern.de/uploads/tx_templavoila/Forschungsbericht_Epicombing_Zillner_figure1.jpg)</p> <p><img src="https://sites.tufts.edu/epigenetics/files/2014/11/methmaintenence1-e1418413999180.png" />(https://sites.tufts.edu/epigenetics/files/2014/11/methmaintenence1-e1418413999180.png)</p> <p> </p> <ul> <li> <h3>Histone modification</h3> </li></olul> <p>More than 50 kinds of histone modifications have been known.</p> <p>Most well known example is histone acetylation</p> <p>Histone acetylation is the process that lysine resides from the histone core of the nucleosome are acetylated by histone acetyltransferase</p> <p>Scientists encounter a problem that which kind of combination is used for gene activation or gene inactivation.</p>
<h2>Why is it important ? >>> Epigenetic modifications regulate gene activity and expression during development and differentiation, or in response to environmental stimuli</h2>
<h2>Epigenetics is considered a bridge between genotype and phenotype</h2>
<h2>Explain how cells carrying identical DNA differentiate into different cell types >>> Epigenetics</h2>
<h2>Epigenome - global analyses of epigenetic markers across the entire genome</h2>
<h2>Chromatin - Histone protein / DNA complex in eukaryotic cells</h2>
<p>Basic Unit - nucleosome - 146 bp of DNA wrapped around an octamer of the four core histones (H2A, H2B, H3 and H4)</p>
<ol>
<li>Euchromatin - transcriptionally active state - the region where DNA is accessible due to the relaxed state of nucleosome arrangement</li>
<li>Heterochromatin - transcriptionally inactive state - the area where DNA is packed into highly condensed forms that are inaccessible to transcription factors</li>
</ol>
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<h2>Epigenome How to regulate Protein Synthesis - global analyses Epigenetic inheritance controls the amount of the transcribed mRNA. Thus, protein production is regulated.</h2> <h4>Ex) Alcohol dehydrogenase (ADH) breaks down alcohol in liver cells.</h4> <h4>We could increase the mRNA of <em>ADH</em> and then make ADH more than usual when we drink much</h4> <h2>Only 2 % of human genome encodes protein and the other 98% controls gene expression by epigenetic markers across mechanism.</h2> <h2>Application</h2> <p>1. Neurological defects could be recovered by correctly recognizing DNA methylation pettern<sup>4)</sup></p> <p>Rett syndrome, one of the entire genomesevere mental retardation diseases, is mostly caused by <em>MeCP2</em> mutation</p> <p>MeCP2 is a protein that decodes DNA methylated regions. If <em>MeCP2 </em>is mutated, we cannot decode these epigenetic codes.</p> <p>There is a vidio <sup>5) </sup>about recovering mentar redardation by activating normal <em>MeCP2</em> gene using certain chemacals in a mouce.</p> <p>It suggests that we could develop therapies for diverse mental development disorders by studying epigenetics in the future.</p> <h2>How could epigenetic inheritance lead monozygotic twins to different ways?</h2> <h3>The Power of Random Epigenetic Modification - X chromosome inactivation</h3> <p>One of the copies of X chromosome in a woman is inactivated by random selection</p> <p>When one woman has a mutation gene in one x chromosome, it could be recovered by the other x chromosome.</p> <p>For example, Duchenne dystrophy is a severe muscular atrophy. It results from X chromosome-related <em>DYSTROPHIN</em> mutation<sup>6)</sup></p> <p>Most of the heterozygous women who have only one <em>DYSTROPHIN</em> mutation gene don't show the symptom because they have the cells which select normal <em>DYSTROPHIN</em> gene and the cells can help nearby mutated cells</p>
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<h2>Chromatin Reference</h2> <p>1) Bird, Adrian P. "CpG-rich islands and the function of DNA methylation." <em>Nature</em>321.6067 (1985): 209- Histone 213.</p> <p>2) Meehan, Richard, Joe D. Lewis, and Adrian P. Bird. "Characterization of MeCP2, a vertebrate DNA binding protein with affinity for methylated DNA."<em>Nucleic acids research</em> 20.19 (1992): 5085-5092.</ DNA p> <p>3) Nan, Xinsheng, et al. "Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex." <em>Nature</em> 393.6683 (1998): 386-389.</p> <p>4) Guy, Jacky, et al. "Reversal of neurological defects in eukaryotic cellsa mouse model of Rett syndrome." <em>Science</h2em> 315.5815 (2007): 1143-1147.</p>
<p>5) https://www.youtube.com/watch?v=RyAvKGmAElQ&feature=related</p>
<p> 6) Nessa, Carey. <strong>The Epigenetics Revolution</strong>, 247p, Bookhouse Publishers, 2011</p>
