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| - | <o:Author>Wendell Lim</o:Author>
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| - | <p class=MsoNormal style='margin-left:.5in;text-indent:-.5in'><span
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| - | style='font-size:11.0pt;font-family:Arial'><b>Q. How is control of gene
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| - | expression by chromatin different from control by transcription factors (and
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| - | what are its advantages)?<o:p></o:p></b></span></p>
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| - |
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| - | <p class=MsoNormal style='margin-left:.5in;text-indent:-.5in'><span
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| - | style='font-size:11.0pt;font-family:Arial'><b><![if !supportEmptyParas]> <![endif]><o:p></o:p></b></span></p>
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| - | <p class=MsoNormal><span style='font-size:11.0pt;font-family:Arial'><b>A.
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| - | Chromatin is a completely different level of gene expression control.<o:p></o:p></b></span></p>
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| - |
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| - | <p class=MsoListBullet2 style='margin-left:1.0in;mso-list:l1 level2 lfo5;
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| - | tab-stops:list 1.0in'><![if !supportLists]><span style='font-size:11.0pt;
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| - | font-family:Symbol'>·<span style='font:7.0pt "Times New Roman"'>
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| - | </span></span><![endif]><span style='font-size:11.0pt'>Dominant over
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| - | transcription factors (resistant to noise).<o:p></o:p></span></p>
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| - |
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| - | <p class=MsoListBullet2 style='margin-left:1.0in;mso-list:l1 level2 lfo5;
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| - | tab-stops:list 1.0in'><![if !supportLists]><span style='font-size:11.0pt;
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| - | font-family:Symbol'>·<span style='font:7.0pt "Times New Roman"'>
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| - | </span></span><![endif]><span style='font-size:11.0pt'>Regional –
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| - | silences domains, not individual genes (reduces the engineering required for
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| - | regulation of complex multi-gene systems).<o:p></o:p></span></p>
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| - |
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| - | <p class=MsoListBullet2 style='margin-left:1.0in;mso-list:l1 level2 lfo5;
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| - | tab-stops:list 1.0in'><![if !supportLists]><span style='font-size:11.0pt;
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| - | font-family:Symbol'>·<span style='font:7.0pt "Times New Roman"'>
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| - | </span></span><![endif]><span style='font-size:11.0pt'>Memory–Alteration
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| - | in gene expression lasts for multiple generations (epigenetic control).<o:p></o:p></span></p>
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| - |
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| - | <p class=MsoListBullet2 style='margin-left:1.0in;mso-list:l1 level2 lfo5;
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| - | tab-stops:list 1.0in'><![if !supportLists]><span style='font-size:11.0pt;
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| - | font-family:Symbol'>·<span style='font:7.0pt "Times New Roman"'>
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| - | </span></span><![endif]><span style='font-size:11.0pt'>Intrinsically bistable,
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| - | i.e. all-or-none expression (increases parameter space over which circuits are
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| - | predicted to be stable).<o:p></o:p></span></p>
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| - |
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| - | <p class=MsoNormal><span style='font-size:11.0pt;font-family:Arial'><![if !supportEmptyParas]> <![endif]><o:p></o:p></span></p>
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| - |
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| - | <p class=MsoNormal><span style='font-size:11.0pt;font-family:Arial'><![if !supportEmptyParas]> <![endif]><o:p></o:p></span></p>
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| - |
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| - | <p class=MsoNormal style='margin-left:.5in;text-indent:-.5in'><span
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| - | style='font-size:11.0pt;font-family:Arial'><b>Q. What applications could this
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| - | type of synthetic chromatin control system be used for?<o:p></o:p></b></span></p>
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| - |
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| - | <p class=MsoNormal><span style='font-size:11.0pt;font-family:Arial'><b><![if !supportEmptyParas]> <![endif]><o:p></o:p></b></span></p>
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| - |
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| - | <p class=MsoNormal><span style='font-size:11.0pt;font-family:Arial'><b>A. To
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| - | stably and permanently switch cells between different states characterized by
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| - | significant differences in gene expression (i.e. cellular differentiation).<o:p></o:p></b></span></p>
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| - |
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| - | <p class=MsoListBullet2 style='margin-left:1.0in;mso-list:l2 level2 lfo7;
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| - | tab-stops:list 1.0in'><![if !supportLists]><span style='font-size:11.0pt;
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| - | font-family:Symbol'>·<span style='font:7.0pt "Times New Roman"'>
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| - | </span></span><![endif]><span style='font-size:11.0pt'>In
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| - | bio-production–for coordinated switching between a growth phase and a
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| - | production phase.<o:p></o:p></span></p>
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| - |
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| - | <p class=MsoListBullet2 style='margin-left:1.0in;mso-list:l3 level1 lfo9;
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| - | tab-stops:list 1.0in'><![if !supportLists]><span style='font-size:11.0pt;
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| - | font-family:Symbol'>·<span style='font:7.0pt "Times New Roman"'>
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| - | </span></span><![endif]><span style='font-size:11.0pt'>In
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| - | bio-production–to differentiate a clonal population of cells into a
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| - | distribution of subtypes that function cooperatively (“factory” with different
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| - | specialized “workers”).<o:p></o:p></span></p>
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| - |
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| - | <p class=MsoListBullet2 style='margin-left:1.0in;mso-list:l1 level2 lfo5;
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| - | tab-stops:list 1.0in'><![if !supportLists]><span style='font-size:11.0pt;
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| - | font-family:Symbol'>·<span style='font:7.0pt "Times New Roman"'>
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| - | </span></span><![endif]><span style='font-size:11.0pt'>To reprogram cell fate
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| - | in a highly specific manner (e.g. stem cell engineering, correction of
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| - | epigenetic abnormalities in cancer cells).<o:p></o:p></span></p>
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| - |
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| - | <p class=MsoListBullet2 style='margin-left:1.0in;mso-list:l1 level2 lfo5;
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| - | tab-stops:list 1.0in'><![if !supportLists]><span style='font-size:11.0pt;
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| - | font-family:Symbol'>·<span style='font:7.0pt "Times New Roman"'>
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| - | </span></span><![endif]><span style='font-size:11.0pt'>To create cells with
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| - | highly digital computational capabilities.<o:p></o:p></span></p>
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| - |
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| - | <p class=MsoListBullet2 style='margin-left:1.0in;mso-list:l1 level2 lfo5;
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| - | tab-stops:list 1.0in'><![if !supportLists]><span style='font-size:11.0pt;
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| - | font-family:Symbol'>·<span style='font:7.0pt "Times New Roman"'>
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| - | </span></span><![endif]><span style='font-size:11.0pt'>To study chromatin
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| - | spreading mechanism in a quantitative and controlled way.<o:p></o:p></span></p>
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| - |
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| - | <p class=MsoNormal style='margin-left:.25in'><span style='font-size:11.0pt;
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| - | font-family:Arial'><![if !supportEmptyParas]> <![endif]><o:p></o:p></span></p>
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| - |
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| - | <p class=MsoNormal style='margin-left:.25in'><span style='font-size:11.0pt;
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| - | font-family:Arial'><![if !supportEmptyParas]> <![endif]><o:p></o:p></span></p>
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| - |
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| - | <p class=MsoNormal><span style='font-size:11.0pt;font-family:Arial'><b>Q. Could
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| - | this type of yeast synthetic chromatin control system be utilized in other cell
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| - | types, including mammalian cells?<o:p></o:p></b></span></p>
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| - |
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| - | <p class=MsoNormal><span style='font-size:11.0pt;font-family:Arial'><b><![if !supportEmptyParas]> <![endif]><o:p></o:p></b></span></p>
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| - |
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| - | <p class=MsoNormal><span style='font-size:11.0pt;font-family:Arial'><b>A. Yes,
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| - | the approach should be transferable.<o:p></o:p></b></span></p>
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| - |
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| - | <p class=MsoListBullet2 style='margin-left:1.0in;mso-list:l1 level2 lfo5;
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| - | tab-stops:list 1.0in'><![if !supportLists]><span style='font-size:11.0pt;
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| - | font-family:Symbol'>·<span style='font:7.0pt "Times New Roman"'>
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| - | </span></span><![endif]><span style='font-size:11.0pt'>Core elements of this
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| - | system are: initiator, covalent mark, spreading (polymerization).<o:p></o:p></span></p>
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| - |
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| - | <p class=MsoListBullet2 style='margin-left:1.0in;mso-list:l1 level2 lfo5;
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| - | tab-stops:list 1.0in'><![if !supportLists]><span style='font-size:11.0pt;
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| - | font-family:Symbol'>·<span style='font:7.0pt "Times New Roman"'>
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| - | </span></span><![endif]><span style='font-size:11.0pt'>In <i>S. cerevisiae</i></span><span
| |
| - | style='font-size:11.0pt'>, covalent mark is deacetylation–we use an
| |
| - | initiator (LexA-Sir2) that when localized deacetylates adjacent histones.<span
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| - | style="mso-spacerun: yes"> </span>This leads to further recruitment of
| |
| - | Sir2, which propagates the mark outward. Deacetylated chromatin adopts a
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| - | “closed” conformation. <o:p></o:p></span></p>
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| - |
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| - | <p class=MsoListBullet2 style='margin-left:1.0in;mso-list:l1 level2 lfo5;
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| - | tab-stops:list 1.0in'><![if !supportLists]><span style='font-size:11.0pt;
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| - | font-family:Symbol'>·<span style='font:7.0pt "Times New Roman"'>
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| - | </span></span><![endif]><span style='font-size:11.0pt'>For higher eukaryotes,
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| - | from <i>S. pombe</i></span><span style='font-size:11.0pt'> to human, the
| |
| - | covalent mark is methylation, initiator is a histone methyltransferase. But in
| |
| - | principle, a similar system should work.<span style="mso-spacerun: yes">
| |
| - | </span>Same logical design, with different catalytic functions propagating
| |
| - | spread.<o:p></o:p></span></p>
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| - |
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| - | <p class=MsoNormal><span style='font-size:11.0pt;font-family:Arial'><span
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| - | style="mso-spacerun: yes"> </span><o:p></o:p></span></p>
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