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Trans-regulatory element
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<h2 id="trans-vs-cis-elements">Trans vs cis elements</h2> <p>Trans-regulatory elements work through an <a href="/facts/Intermolecular_force/xIcFMvL7">intermolecular</a> interaction between two different molecules and so are said to be "<a href="/facts/Trans-acting/4VfDEHnR">acting in trans</a>". For example (1) a <a href="/facts/Transcription_(genetics)/bDgp9HDN">transcribed</a> and <a href="/facts/Translation_(biology)/JcPC1rth">translated</a> <a href="/facts/Transcription_factor/wro0DPHe">transcription factor</a> protein derived from the trans-regulatory element; and a (2) DNA <a href="/facts/Regulatory_sequence/8jstgLKD">regulatory element</a> that is adjacent to the regulated gene. This is in contrast to <a href="/facts/Cis-regulatory_element/q6u6VSBs">cis-regulatory elements</a> that work through an <a href="/facts/Intramolecular_force/f2Wxm1l3">intramolecular</a> interaction between different parts of the same molecule: (1) a gene; and (2) an adjacent regulatory element for that gene in the same DNA molecule. Additionally, each trans-regulatory element affects a large number of genes on both alleles,<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> while cis-regulatory element is allele specific <a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a><a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> and only controls genes nearby. </p><p><a href="/facts/Exon/8KWJtLuN">Exonic</a> and <a href="/facts/Promoter_(genetics)/YDYBzLfg">promoter</a> sequences of the genes are significantly more conserved than the genes in cis- and trans- regulatory elements.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> Hence, they have higher resistance to genetic divergence, yet retains its susceptibility to mutations in upstream regulators.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> This accentuates the significance of genetic divergence within species due to cis- and trans-regulatory variants. </p><p>Trans- and cis-regulatory elements co-evolved rapidly in large-scale to maintain gene expression.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a><a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a><a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> They often act in opposite directions, one up-regulates while another down-regulates, to compensate for their effects on the exonic and promoter sequences they act on.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a><a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> Other evolutionary models, such as the independent evolution of trans- or cis-regulatory elements, were deemed incompatible in regulatory systems.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a><a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> Co-evolution of the two regulatory elements was suggested to arise from the same lineage.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a><a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> </p><p>TRE is more evolutionary constraint than cis-regulatory element, suggesting a hypothesis that TRE mutations are corrected by CRE mutations<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> to maintain stability in gene expression. This makes biological sense, due to TRE's effect on a broad range of genes and CRE's compensatory effect on specific genes.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a><a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> Following a TRE mutation, accumulation of CRE mutations act to fine-tune the mutative effect.<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> </p> <h2 id="examples">Examples</h2> <p>Trans-acting factors can be categorized by their interactions with the regulated genes, cis-acting elements of the genes, or the gene products. </p> <h3>DNA binding</h3> <p>DNA binding trans-acting factors regulate gene expression by interfering with the gene itself or cis-acting elements of the gene, which lead to changes in transcription activities. This can be direct initiation of transcription,<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> promotion, or repression of transcriptional protein activities.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> </p><p>Specific examples include: </p> <ul><li><a href="/facts/Transcription_factor/wro0DPHe">Transcription factors</a></li></ul> <h3>DNA editing</h3> <p>DNA editing proteins edit and permanently change gene sequence, and subsequently the gene expression of the cell.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a><a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> All progenies of the cell will inherit the edited gene sequence.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> DNA editing proteins often take part in the immune response system of both prokaryotes and eukaryotes, providing high variance in gene expression in adaptation to various pathogens.<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> </p><p>Specific examples include: </p> <ul><li><a href="/facts/RAG1/eyVKermm">RAG1</a>/<a href="/facts/RAG2/A2Gm1zVv">RAG2</a></li> <li><a href="/facts/Terminal_deoxynucleotidyl_transferase/eKh9h60n">TdT</a></li> <li><a href="/facts/Cas1/jJLcnsvF">Cas1</a>/<a href="/facts/Cas2/WSKYw4Ls">Cas2</a></li></ul> <h3>mRNA processing</h3> <p class="note">Main article: <a href="/facts/Messenger_RNA/oUL6qxQn">Messenger RNA</a></p> <p>mRNA processing acts as a form of post-transcriptional regulation, which mostly happens in eukaryotes. 3′ cleavage/polyadenylation and 5’ capping increase overall RNA stability, and the presence of 5’ cap allows ribosome binding for translation. RNA splicing allows the expression of various protein variants from the same gene.<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> </p><p>Specific examples include: </p> <ul><li><a href="/facts/SR_protein/PjScA00d">SR proteins</a></li> <li><a href="/facts/Ribonucleoprotein/S07sU6hq">Ribonucleoprotein</a> <ul><li><a href="/facts/Hnrnp/YrbVK8r9">hnRNP</a></li> <li><a href="/facts/SnRNP/oj1C18HB">snRNP</a></li></ul></li></ul> <h3>mRNA binding</h3> <p>mRNA binding allows repression of protein translation through direct blocking, degradation or cleavage of mRNA.<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a><a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> Certain mRNA binding mechanisms have high specificity, which can act as a form of the intrinsic immune response during certain viral infections.<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a> Certain segmented RNA viruses can also regulate viral gene expression through RNA binding of another genome segment, however, the details of this mechanism are still unclear.<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a> </p><p>Specific examples include: </p> <ul><li><a href="/facts/RNA-binding_protein/qTPTczLC">RNA binding protein</a></li> <li><a href="/facts/Small_interfering_RNA/891ytkD9">siRNA</a></li> <li><a href="/facts/MicroRNA/UjqbYYpe">miRNA</a></li> <li><a href="/facts/Piwi-interacting_RNA/5JXza7t8">piRNA</a></li></ul> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/Cis-regulatory_element/q6u6VSBs">Cis-regulatory element</a></li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Gilad Y, Rifkin SA, Pritchard JK (August 2008). "Revealing the architecture of gene regulation: the promise of eQTL studies". Trends in Genetics. 24 (8): 408–15. doi:10.1016/j.tig.2008.06.001. PMC 2583071. PMID 18597885. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583071" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583071</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Wang Q, Jia Y, Wang Y, Jiang Z, Zhou X, Zhang Z, Nie C, Li J, Yang N, Qu L (December 2019). "Evolution of cis- and trans-regulatory divergence in the chicken genome between two contrasting breeds analyzed using three tissue types at one-day-old". BMC Genomics. 20 (1): 933. doi:10.1186/s12864-019-6342-5. PMC 6896592. PMID 31805870. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896592" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896592</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Goncalves A, Leigh-Brown S, Thybert D, Stefflova K, Turro E, Flicek P, Brazma A, Odom DT, Marioni JC (December 2012). "Extensive compensatory cis-trans regulation in the evolution of mouse gene expression". Genome Research. 22 (12): 2376–84. doi:10.1101/gr.142281.112. PMC 3514667. PMID 22919075. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514667" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514667</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Goncalves A, Leigh-Brown S, Thybert D, Stefflova K, Turro E, Flicek P, Brazma A, Odom DT, Marioni JC (December 2012). "Extensive compensatory cis-trans regulation in the evolution of mouse gene expression". Genome Research. 22 (12): 2376–84. doi:10.1101/gr.142281.112. PMC 3514667. PMID 22919075. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514667" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514667</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Wang Q, Jia Y, Wang Y, Jiang Z, Zhou X, Zhang Z, Nie C, Li J, Yang N, Qu L (December 2019). "Evolution of cis- and trans-regulatory divergence in the chicken genome between two contrasting breeds analyzed using three tissue types at one-day-old". BMC Genomics. 20 (1): 933. doi:10.1186/s12864-019-6342-5. PMC 6896592. PMID 31805870. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896592" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896592</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Gilad Y, Rifkin SA, Pritchard JK (August 2008). "Revealing the architecture of gene regulation: the promise of eQTL studies". Trends in Genetics. 24 (8): 408–15. doi:10.1016/j.tig.2008.06.001. PMC 2583071. PMID 18597885. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583071" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583071</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Wang Q, Jia Y, Wang Y, Jiang Z, Zhou X, Zhang Z, Nie C, Li J, Yang N, Qu L (December 2019). "Evolution of cis- and trans-regulatory divergence in the chicken genome between two contrasting breeds analyzed using three tissue types at one-day-old". BMC Genomics. 20 (1): 933. doi:10.1186/s12864-019-6342-5. PMC 6896592. PMID 31805870. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896592" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896592</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Goncalves A, Leigh-Brown S, Thybert D, Stefflova K, Turro E, Flicek P, Brazma A, Odom DT, Marioni JC (December 2012). "Extensive compensatory cis-trans regulation in the evolution of mouse gene expression". Genome Research. 22 (12): 2376–84. doi:10.1101/gr.142281.112. PMC 3514667. PMID 22919075. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514667" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514667</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Goncalves A, Leigh-Brown S, Thybert D, Stefflova K, Turro E, Flicek P, Brazma A, Odom DT, Marioni JC (December 2012). "Extensive compensatory cis-trans regulation in the evolution of mouse gene expression". Genome Research. 22 (12): 2376–84. doi:10.1101/gr.142281.112. PMC 3514667. PMID 22919075. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514667" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514667</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Wang Q, Jia Y, Wang Y, Jiang Z, Zhou X, Zhang Z, Nie C, Li J, Yang N, Qu L (December 2019). "Evolution of cis- and trans-regulatory divergence in the chicken genome between two contrasting breeds analyzed using three tissue types at one-day-old". BMC Genomics. 20 (1): 933. doi:10.1186/s12864-019-6342-5. PMC 6896592. PMID 31805870. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896592" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896592</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>Goncalves A, Leigh-Brown S, Thybert D, Stefflova K, Turro E, Flicek P, Brazma A, Odom DT, Marioni JC (December 2012). "Extensive compensatory cis-trans regulation in the evolution of mouse gene expression". Genome Research. 22 (12): 2376–84. doi:10.1101/gr.142281.112. PMC 3514667. PMID 22919075. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514667" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514667</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>McManus CJ, Coolon JD, Duff MO, Eipper-Mains J, Graveley BR, Wittkopp PJ (June 2010). "Regulatory divergence in Drosophila revealed by mRNA-seq". Genome Research. 20 (6): 816–25. doi:10.1101/gr.102491.109. PMC 2877578. PMID 20354124. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877578" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877578</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Wang Q, Jia Y, Wang Y, Jiang Z, Zhou X, Zhang Z, Nie C, Li J, Yang N, Qu L (December 2019). "Evolution of cis- and trans-regulatory divergence in the chicken genome between two contrasting breeds analyzed using three tissue types at one-day-old". BMC Genomics. 20 (1): 933. doi:10.1186/s12864-019-6342-5. PMC 6896592. PMID 31805870. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896592" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896592</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>Goncalves A, Leigh-Brown S, Thybert D, Stefflova K, Turro E, Flicek P, Brazma A, Odom DT, Marioni JC (December 2012). "Extensive compensatory cis-trans regulation in the evolution of mouse gene expression". Genome Research. 22 (12): 2376–84. doi:10.1101/gr.142281.112. PMC 3514667. PMID 22919075. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514667" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514667</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>Goncalves A, Leigh-Brown S, Thybert D, Stefflova K, Turro E, Flicek P, Brazma A, Odom DT, Marioni JC (December 2012). "Extensive compensatory cis-trans regulation in the evolution of mouse gene expression". Genome Research. 22 (12): 2376–84. doi:10.1101/gr.142281.112. PMC 3514667. PMID 22919075. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514667" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514667</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>Landry CR, Wittkopp PJ, Taubes CH, Ranz JM, Clark AG, Hartl DL (December 2005). "Compensatory cis-trans evolution and the dysregulation of gene expression in interspecific hybrids of Drosophila". Genetics. 171 (4): 1813–22. doi:10.1534/genetics.105.047449. PMC 1456106. PMID 16143608. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1456106" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1456106</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></p></li> <li id="fn:17"><p>Goncalves A, Leigh-Brown S, Thybert D, Stefflova K, Turro E, Flicek P, Brazma A, Odom DT, Marioni JC (December 2012). "Extensive compensatory cis-trans regulation in the evolution of mouse gene expression". Genome Research. 22 (12): 2376–84. doi:10.1101/gr.142281.112. PMC 3514667. PMID 22919075. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514667" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514667</a> <a href="#fnref:17" class="footnote-back-ref">↩</a></p></li> <li id="fn:18"><p>McManus CJ, Coolon JD, Duff MO, Eipper-Mains J, Graveley BR, Wittkopp PJ (June 2010). "Regulatory divergence in Drosophila revealed by mRNA-seq". Genome Research. 20 (6): 816–25. doi:10.1101/gr.102491.109. PMC 2877578. PMID 20354124. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877578" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877578</a> <a href="#fnref:18" class="footnote-back-ref">↩</a></p></li> <li id="fn:19"><p>Goncalves A, Leigh-Brown S, Thybert D, Stefflova K, Turro E, Flicek P, Brazma A, Odom DT, Marioni JC (December 2012). "Extensive compensatory cis-trans regulation in the evolution of mouse gene expression". Genome Research. 22 (12): 2376–84. doi:10.1101/gr.142281.112. PMC 3514667. PMID 22919075. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514667" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514667</a> <a href="#fnref:19" class="footnote-back-ref">↩</a></p></li> <li id="fn:20"><p>Gilad Y, Rifkin SA, Pritchard JK (August 2008). "Revealing the architecture of gene regulation: the promise of eQTL studies". Trends in Genetics. 24 (8): 408–15. doi:10.1016/j.tig.2008.06.001. PMC 2583071. PMID 18597885. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583071" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583071</a> <a href="#fnref:20" class="footnote-back-ref">↩</a></p></li> <li id="fn:21"><p>Wang Q, Jia Y, Wang Y, Jiang Z, Zhou X, Zhang Z, Nie C, Li J, Yang N, Qu L (December 2019). "Evolution of cis- and trans-regulatory divergence in the chicken genome between two contrasting breeds analyzed using three tissue types at one-day-old". BMC Genomics. 20 (1): 933. doi:10.1186/s12864-019-6342-5. PMC 6896592. PMID 31805870. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896592" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896592</a> <a href="#fnref:21" class="footnote-back-ref">↩</a></p></li> <li id="fn:22"><p>Goncalves A, Leigh-Brown S, Thybert D, Stefflova K, Turro E, Flicek P, Brazma A, Odom DT, Marioni JC (December 2012). "Extensive compensatory cis-trans regulation in the evolution of mouse gene expression". Genome Research. 22 (12): 2376–84. doi:10.1101/gr.142281.112. PMC 3514667. PMID 22919075. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514667" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514667</a> <a href="#fnref:22" class="footnote-back-ref">↩</a></p></li> <li id="fn:23"><p>Griffiths AJ, Miller JH, Suzuki DT, Lewontin RC, Gelbart WM (2000). "Transcription and RNA polymerase". An Introduction to Genetic Analysis (7th ed.). New York: W. H. Freeman. ISBN 978-0-7167-3520-5. <a href="978-0-7167-3520-5" target="_blank">978-0-7167-3520-5</a> <a href="#fnref:23" class="footnote-back-ref">↩</a></p></li> <li id="fn:24"><p>Lodish H, Berk A, Zipursky SL, Berk A, Darnell JE, Zipursky SL, Baltimore D, Matsudaira P (2000). "Section 10.5: Eukaryotic Transcription Activators and Repressors". Molecular Cell Biology (4th ed.). New York: W. H. Freeman. ISBN 978-0-7167-3136-8. <a href="978-0-7167-3136-8" target="_blank">978-0-7167-3136-8</a> <a href="#fnref:24" class="footnote-back-ref">↩</a></p></li> <li id="fn:25"><p>Roth DB (December 2014). 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