Trans-regulatory element

Trans-regulatory elements (TRE) are DNA sequences encoding upstream regulators (ie. trans-acting factors), which may modify or regulate the expression of distant genes.[1] Trans-acting factors interact with cis-regulatory elements to regulate gene expression.[2] TRE mediates expression profiles of a large number of genes via trans-acting factors.[3] While TRE mutations affect gene expression, it is also one of the main driving factors for evolutionary divergence in gene expression.[3]

Trans vs cis elements

Trans-regulatory elements work through an intermolecular interaction between two different molecules and so are said to be "acting in trans". For example (1) a transcribed and translated transcription factor protein derived from the trans-regulatory element; and a (2) DNA regulatory element that is adjacent to the regulated gene. This is in contrast to cis-regulatory elements that work through an intramolecular 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,[2] while cis-regulatory element is allele specific [1][2] and only controls genes nearby.

Exonic and promoter sequences of the genes are significantly more conserved than the genes in cis- and trans- regulatory elements.[3] Hence, they have higher resistance to genetic divergence, yet retains its susceptibility to mutations in upstream regulators.[3] This accentuates the significance of genetic divergence within species due to cis- and trans-regulatory variants.

Trans- and cis-regulatory elements co-evolved rapidly in large-scale to maintain gene expression.[2][3][4] They often act in opposite directions, one up-regulates while another down-regulates, to compensate for their effects on the exonic and promoter gene they act on.[2][3] Other evolutionary models, such as the independent evolution of trans- or cis-regulatory elements, were deemed incompatible in regulatory systems.[3][5] Co-evolution of the two regulatory elements was suggested to arise from the same lineage.[3][4]

TRE is more evolutionary constraint than cis-regulatory element, suggesting a hypothesis that TRE mutations are corrected by CRE mutations[3] 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.[1][2] Following a TRE mutation, accumulation of CRE mutations act to fine-tune the mutative effect.[3]

Examples
Trans-acting factors in alternative splicing in mRNA. Alternative splicing is a key mechanism that is involved in gene expression regulation. In the alternative splicing, trans-acting factors such as SR protein, hnRNP and snRNP control this mechanism by acting in trans. SR protein promotes the spliceosome assembly by interacting with snRNP(e.g. U1, U2) and splicing factors(e.g. U2AF65), and it can also antagonize the activity of hnRNP that inhibits splicing.

Trans-acting factors can be categorized by their interactions with the regulated genes, cis-acting elements of the genes, or the gene products.

DNA binding

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.[6] promotion or repression of transcriptional protein activities.[7]

Specific examples include:

DNA editing

DNA editing proteins edit and permanently change gene sequence, and subsequently the gene expression of the cell.[8][9] All progenies of the cell will inherit the edited gene sequence.[10] 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.[11]

Specific examples include:

mRNA processing
Main article: Messenger RNA

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.[12]

Specific examples include:

mRNA binding

mRNA binding allows repression of protein translation through direct blocking, degradation or cleavage of mRNA.[13][14] Certain mRNA binding mechanisms have high specificity, which can act as a form of the intrinsic immune response during certain viral infections.[15] 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.[16]

Specific examples include:

See also

References
  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. Roth DB (December 2014). "V(D)J Recombination: Mechanism, Errors, and Fidelity". Microbiology Spectrum. 2 (6): 313–324. doi:10.1128/microbiolspec.MDNA3-0041-2014. ISBN 9781555819200. PMC 5089068. PMID 26104458.
  9. McGinn J, Marraffini LA (January 2019). "Molecular mechanisms of CRISPR-Cas spacer acquisition". Nature Reviews. Microbiology. 17 (1): 7–12. doi:10.1038/s41579-018-0071-7. PMID 30171202. S2CID 52139589.
  10. Janeway Jr CA, Travers P, Walport M, Schlomchik M (2001). "B-cell activation by armed helper T cells". Immunobiology: The Immune System in Health and Disease (5th ed.). New York: Garland Science. ISBN 978-0-8153-3642-6.
  11. Janeway Jr CA, Travers P, Walport M, Schlomchik M (2001). "The generation of diversity in immunoglobulins". Immunobiology: The Immune System in Health and Disease (5th ed.). New York: Garland Science. ISBN 978-0-8153-3642-6.
  12. Lodish H, Berk A, Zipursky SL, Berk A, Darnell JE, Zipursky SL, Baltimore D, Matsudaira P (2000). "Section 11.2: Processing of Eukaryotic mRNA". Molecular Cell Biology (4th ed.). New York: W. H. Freeman. ISBN 978-0-7167-3136-8.
  13. Dana H, Chalbatani GM, Mahmoodzadeh H, Karimloo R, Rezaiean O, Moradzadeh A, Mehmandoost N, Moazzen F, Mazraeh A, Marmari V, Ebrahimi M, Rashno MM, Abadi SJ, Gharagouzlo E (June 2017). "Molecular Mechanisms and Biological Functions of siRNA". International Journal of Biomedical Science : IJBS. 13 (2): 48–57. PMC 5542916. PMID 28824341.
  14. Wahid F, Shehzad A, Khan T, Kim YY (November 2010). "MicroRNAs: synthesis, mechanism, function, and recent clinical trials". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1803 (11): 1231–43. doi:10.1016/j.bbamcr.2010.06.013. PMID 20619301.
  15. Guo XK, Zhang Q, Gao L, Li N, Chen XX, Feng WH (January 2013). "Increasing expression of microRNA 181 inhibits porcine reproductive and respiratory syndrome virus replication and has implications for controlling virus infection". Journal of Virology. 87 (2): 1159–71. doi:10.1128/JVI.02386-12. PMC 3554091. PMID 23152505.
  16. Newburn LR, White KA (August 2019). "Trans-Acting RNA-RNA Interactions in Segmented RNA Viruses". Viruses. 11 (8): 751. doi:10.3390/v11080751. PMC 6723669. PMID 31416187.


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