User:McDonell "Chemical Burger" Miller/sandbox

Trans-regulatory element for Wikipedia Draft

Brief description (Introduction)

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].

Function (Introduction)

Trans-acting factors interact with cis-regulatory elements to regulate gene expression [3]. TRE mediates expression profiles of a large number of genes via trans-acting factors [2].

While mutations in TRE affect gene expression, it is also one of the main driving factors for divergence in gene expression evolution [2].

Trans- vs Cis- Regulatory Elements (Introduction)

“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.” - from Wikipedia page. Additionally, each trans-regulatory element affects a large number of genes on both alleles, while  cis-regulatory elements are gene and allele specific [1,3].

Co-evolution of Trans- vs Cis- Regulatory Elements (New Section)

Exonic and promoter sequences of the genes are significantly more conserved than the genes in cis- and trans- regulatory; hence, they are more resistant to gradual genetic divergence but remain vulnerable to regulation of upstream regulators [2]. This accentuates the significance of genetic divergence within species due to cis- and trans- regulatory elements.

Trans- and cis- regulatory elements co-evolved rapidly and in large-scale to maintain gene expression [2,3,6]. 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 independent evolution of trans- or cis- regulatory elements, was deemed incompatible in regulatory systems [5, 6]. Co-evolution of the two regulatory elements (trans- and cis-) were suggested to arise from the same lineage [2, 6].

TRE are more evolutionary constraint than cis- regulatory element, suggesting a hypothesis that TRE mutations are corrected by CRE mutations [2] to maintain stability in gene expression. This makes biological sense due to TRE’s effect on a broad range of genes while CRE is gene- and allele- specific [2]. Following TRE mutations, CRE mutations act to fine-tune the mutative effect [2].

Examples of Trans-Regulatory Elements


 * Diffusible elements: proteins and ribonucleic acid (RNA)

[1] Gilad, Y., Rifkin, S. A., & Pritchard, J. K. (2008). Revealing the architecture of gene regulation: the promise of eQTL studies. Trends in genetics : TIG, 24(8), 408–415. https://doi.org/10.1016/j.tig.2008.06.001

[2] Goncalves, A., Leigh-Brown, S., Thybert, D., Stefflova, K., Turro, E., Flicek, P., Brazma, A., Odom, D. T., & Marioni, J. C. (2012). Extensive compensatory cis-trans regulation in the evolution of mouse gene expression. Genome research, 22(12), 2376–2384. https://doi.org/10.1101/gr.142281.112

[3] Wang, Q., Jia, Y., Wang, Y., Jiang, Z., Zhou, X., Zhang, Z.,. . . Qu, L. (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), 933-933. doi:10.1186/s12864-019-6342-5

[5] McManus, C. J., Coolon, J. D., Duff, M. O., Eipper-Mains, J., Graveley, B. R., & Wittkopp, P. J. (2010). Regulatory divergence in drosophila revealed by mRNA-seq. Genome Research, 20(6), 816-825. doi:10.1101/gr.102491.109

[6] Landry, C. R., Wittkopp, P. J., Taubes, C. H., Ranz, J. M., Clark, A. G., & Hartl, D. L. (2005). Compensatory cis-trans evolution and the dysregulation of gene expression in interspecific hybrids of drosophila. Genetics (Austin), 171(4), 1813-1822. doi:10.1534/genetics.105.047449

[7]Griffiths AJF, Miller JH, Suzuki DT, et al. An Introduction to Genetic Analysis. 7th edition. New York: W. H. Freeman; 2000. Transcription and RNA polymerase. Available from: https://www.ncbi.nlm.nih.gov/books/NBK22085/

[8]Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000. Section 10.5, Eukaryotic Transcription Activators and Repressors. Available from: https://www.ncbi.nlm.nih.gov/books/NBK21572/

[9]Roth D. B. (2014). V(D)J Recombination: Mechanism, Errors, and Fidelity. Microbiology spectrum, 2(6), 10.1128/microbiolspec.MDNA3-0041-2014. https://doi.org/10.1128/microbiolspec.MDNA3-0041-2014

[10]McGinn, J., & Marraffini, L. A. (2019). Molecular mechanisms of CRISPR-Cas spacer acquisition. Nature Reviews Microbiology, 17(1), 7. https://link.gale.com/apps/doc/A573274366/HRCA?u=ubcolumbia&sid=HRCA&xid=018cf0ef

[11]Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. B-cell activation by armed helper T cells. Available from: https://www.ncbi.nlm.nih.gov/books/NBK27142/

[12]Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. The generation of diversity in immunoglobulins. Available from: https://www.ncbi.nlm.nih.gov/books/NBK27140/

[13]Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000. Section 11.2, Processing of Eukaryotic mRNA. Available from: https://www.ncbi.nlm.nih.gov/books/NBK21563/

Trans-acting factors can be categorized by its interaction with the regulated gene, cis-acting elements of the gene, or the gene product.

-DNA binding

(Transcription factor, activators/repressors, histones)

{} regulate gene expression by interfering with the gene itself or cis-acting elements of the gene, which lead of changes in transcritoin activities. This can be direct initiation of transcription[1], promotion or repression of transcriptional protein activities[2].

-DNA editing

(RAG1/2, TdT, Crispr)

DNA editing proteins edit and permanently change gene sequence, and subsequently the gene expression of the cell [1,2]. All progenies of the cell will inherit the altered gene sequence[3]. DNA editing proteins often take part in the immune system, providing high variance in gene expression to counter various pathogens[4].

-mRNA processing

(SR proteins, hnRNP)

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 presence of 5’ cap allow ribosome binding for translation. RNA splicing allows expression of various protein variants from the same gene[1].

-mRNA binding

(RBP, siRNA, miRNA, piRNA)

mRNA binding allows repression of protein translation through direct blocking, degradation or cleavage of mRNA.[1,2]. Certain mRNA binding mechanisms have high specificity, which can act as a form of intrinsic immune response during certain viral infections [3]. Certain segmented RNA viruses can also regulate viral gene expression through RNA binding of another genome segment[4].

[1]Dana, H., Chalbatani, G. M., Mahmoodzadeh, H., Karimloo, R., Rezaiean, O., Moradzadeh, A., Mehmandoost, N., Moazzen, F., Mazraeh, A., Marmari, V., Ebrahimi, M., Rashno, M. M., Abadi, S. J., & Gharagouzlo, E. (2017). Molecular Mechanisms and Biological Functions of siRNA. International journal of biomedical science : IJBS, 13(2), 48–57.

[2]Wahid, F., Shehzad, A., Khan, T., & Kim, Y. Y. (2010). MicroRNAs: Synthesis, mechanism, function, and recent clinical trials. Biochimica Et Biophysica Acta (BBA) - Molecular Cell Research, 1803(11), 1231-1243. doi:10.1016/j.bbamcr.2010.06.013

[3]Guo, X. K., Zhang, Q., Gao, L., Li, N., Chen, X. X., & Feng, W. H. (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), 1159–1171. https://doi.org/10.1128/JVI.02386-12

[4]Newburn, L. R., & White, K. A. (2019). Trans-Acting RNA–RNA Interactions in Segmented RNA Viruses. Viruses, 11(8), 751. doi:10.3390/v11080751

* Examples

* Transcription factor

Main article : Transcription factor

Transcription factors are one of the regulatory elements that are not encoded from regulated gene(s)[7]. Transcription factors control gene transcription by binding to DNA or via intermediate protein to the specific DNA sequence called a cis-regulatory region[7]. During the initiation of transcription, trans-acting factors bind to the cis-regulatory regions via interactions between trans-acting factors and RNA polymer complex[7].

[7] Brady, S. T., Siegel, G. J., & Albers, R. W. (2012). Basic neurochemistry: Molecular, cellular, and medical aspects (8th ed.). Amsterdam: Elsevier, 518



Transcription factors are co-activators or co-repressors that are categorized as trans-acting factors because they are regulatory agents that are not part of the regulated gene(s). These trans-acting factors regulate gene transcription by binding directly or through an intermediate protein to the gene at a particular DNA sequence, called a cis-regulatory region. Binding of the trans-acting factor to the cis-regulatory region alters the initiation of transcription, probably through a direct interaction of the trans-acting factor with the RNA polymerase complex.

[1] Brady, S. T., Siegel, G. J., & Albers, R. W. (2012). Basic neurochemistry: Molecular, cellular, and medical aspects (8th ed.). Amsterdam: Elsevier, 518

* RNA Binding Protein

Main article : RNA-binding protein

RNA-binding proteins mediate the post-translational regulation in gene expression[1]. RBPs control mRNA stability and translation to regulate the post-translational regulation[2]. These RBPs bind to mRNA cis-elements through a specific RNA recognistion motif in each RBP, and they [2].

Example : TTP(Tristetraprolin)

The post-transcriptional regulation of gene expression is mediated by both mRNA cis-elements and trans-acting factors such as RNA-binding proteins (RBPs) and microRNAs (miRNAs).

RBPs play an essential role in the post-transcriptional regulation of gene expression by controlling mRNA stability and translation. Each RBP has a specific RNA recognition motif that mediates its binding to mRNA cis-elements. AU-rich elements (AREs) are mRNA cis-elements that promote the destabilization of mRNA transcripts following their deadenylation by deadenylase complexes.

For example, TTP, a well-characterized ARE-binding protein (ARE-BP) inhibits translation by recruiting eIF4E2 to the target mRNA, thereby disrupting the assembly of the eIF4F complex.

[1] https://academic.oup.com/jb/article/161/4/309/2734460

[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4693235/

* miRNA

miRNAs mediate mRNA degradation to control the post-translational regulation in gene expression and molecular mechanisms[1]. miRNA inhibits the translation of mRNA transcripts to control mRNA degradation by forming miRNA-induced silencing complex(miRISC) with Argonaute (Ago) proteins[1]. miRNA can inhibit translation by utilizing independent mechanisms of ribosomal scanning[1].

miRNAs play a key role in the post-transcriptional regulation of gene expression and the molecular mechanism by which miRNAs mediate mRNA degradation-

miRNAs play a key role in the post-transcriptional regulation of gene expression and the molecular mechanism by which miRNAs mediate mRNA degradation has been well characterized.

miRNAs interact with Argonaute (Ago) proteins to form an miRNA-induced silencing complex (miRISC) that inhibits the translation of target mRNA transcripts and mediates mRNA degradation.

miRISC mediates the dissociation of eIF4As from eIF4F prior to the removal of PABP from target mRNAs.

Alternatively, miRNA inhibits translation via a mechanism independent of ribosomal scanning.

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4693235/

+ RBP and miRNA are for post-translational regulation of gene expression, so I added some explanation for these categories. But the contents should be more general for public, so need to change words and add more details.

[1] https://academic.oup.com/jb/article/161/4/309/2734460

* Ribonucleoprotein

-trans-acting splicing factor

-

* SR protein

-trans-acting splicing factor

+ format