Trans-regulatory element

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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]

Contents

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 sequences 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 in alternative splicing.png
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

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

Related Research Articles

<span class="mw-page-title-main">Promoter (genetics)</span> Region of DNA encouraging transcription

In genetics, a promoter is a sequence of DNA to which proteins bind to initiate transcription of a single RNA transcript from the DNA downstream of the promoter. The RNA transcript may encode a protein (mRNA), or can have a function in and of itself, such as tRNA or rRNA. Promoters are located near the transcription start sites of genes, upstream on the DNA . Promoters can be about 100–1000 base pairs long, the sequence of which is highly dependent on the gene and product of transcription, type or class of RNA polymerase recruited to the site, and species of organism.

<span class="mw-page-title-main">RNA splicing</span> Process in molecular biology

RNA splicing is a process in molecular biology where a newly-made precursor messenger RNA (pre-mRNA) transcript is transformed into a mature messenger RNA (mRNA). It works by removing all the introns and splicing back together exons. For nuclear-encoded genes, splicing occurs in the nucleus either during or immediately after transcription. For those eukaryotic genes that contain introns, splicing is usually needed to create an mRNA molecule that can be translated into protein. For many eukaryotic introns, splicing occurs in a series of reactions which are catalyzed by the spliceosome, a complex of small nuclear ribonucleoproteins (snRNPs). There exist self-splicing introns, that is, ribozymes that can catalyze their own excision from their parent RNA molecule. The process of transcription, splicing and translation is called gene expression, the central dogma of molecular biology.

<span class="mw-page-title-main">Transcription factor</span> Protein that regulates the rate of DNA transcription

In molecular biology, a transcription factor (TF) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The function of TFs is to regulate—turn on and off—genes in order to make sure that they are expressed in the desired cells at the right time and in the right amount throughout the life of the cell and the organism. Groups of TFs function in a coordinated fashion to direct cell division, cell growth, and cell death throughout life; cell migration and organization during embryonic development; and intermittently in response to signals from outside the cell, such as a hormone. There are 1500-1600 TFs in the human genome. Transcription factors are members of the proteome as well as regulome.

<span class="mw-page-title-main">Gene expression</span> Conversion of a genes sequence into a mature gene product or products

Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, proteins or non-coding RNA, and ultimately affect a phenotype. These products are often proteins, but in non-protein-coding genes such as transfer RNA (tRNA) and small nuclear RNA (snRNA), the product is a functional non-coding RNA. Gene expression is summarized in the central dogma of molecular biology first formulated by Francis Crick in 1958, further developed in his 1970 article, and expanded by the subsequent discoveries of reverse transcription and RNA replication.

<span class="mw-page-title-main">Alternative splicing</span> Process by which a gene can code for multiple proteins

Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be included within or excluded from the final, processed messenger RNA (mRNA) produced from that gene. This means the exons are joined in different combinations, leading to different (alternative) mRNA strands. Consequently, the proteins translated from alternatively spliced mRNAs usually contain differences in their amino acid sequence and, often, in their biological functions.

<span class="mw-page-title-main">Enhancer (genetics)</span> DNA sequence that binds activators to increase the likelihood of gene transcription

In genetics, an enhancer is a short region of DNA that can be bound by proteins (activators) to increase the likelihood that transcription of a particular gene will occur. These proteins are usually referred to as transcription factors. Enhancers are cis-acting. They can be located up to 1 Mbp away from the gene, upstream or downstream from the start site. There are hundreds of thousands of enhancers in the human genome. They are found in both prokaryotes and eukaryotes.

A regulatory sequence is a segment of a nucleic acid molecule which is capable of increasing or decreasing the expression of specific genes within an organism. Regulation of gene expression is an essential feature of all living organisms and viruses.

<span class="mw-page-title-main">Three prime untranslated region</span> Sequence at the 3 end of messenger RNA that does not code for product

In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation termination codon. The 3′-UTR often contains regulatory regions that post-transcriptionally influence gene expression.

In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from altering the number of copies of RNA that are transcribed, to the temporal control of when the gene is transcribed. This control allows the cell or organism to respond to a variety of intra- and extracellular signals and thus mount a response. Some examples of this include producing the mRNA that encode enzymes to adapt to a change in a food source, producing the gene products involved in cell cycle specific activities, and producing the gene products responsible for cellular differentiation in multicellular eukaryotes, as studied in evolutionary developmental biology.

In molecular biology, the TATA box is a sequence of DNA found in the core promoter region of genes in archaea and eukaryotes. The bacterial homolog of the TATA box is called the Pribnow box which has a shorter consensus sequence.

<span class="mw-page-title-main">Functional genomics</span> Field of molecular biology

Functional genomics is a field of molecular biology that attempts to describe gene functions and interactions. Functional genomics make use of the vast data generated by genomic and transcriptomic projects. Functional genomics focuses on the dynamic aspects such as gene transcription, translation, regulation of gene expression and protein–protein interactions, as opposed to the static aspects of the genomic information such as DNA sequence or structures. A key characteristic of functional genomics studies is their genome-wide approach to these questions, generally involving high-throughput methods rather than a more traditional "candidate-gene" approach.

<span class="mw-page-title-main">Antisense RNA</span>

Antisense RNA (asRNA), also referred to as antisense transcript, natural antisense transcript (NAT) or antisense oligonucleotide, is a single stranded RNA that is complementary to a protein coding messenger RNA (mRNA) with which it hybridizes, and thereby blocks its translation into protein. The asRNAs have been found in both prokaryotes and eukaryotes, and can be classified into short and long non-coding RNAs (ncRNAs). The primary function of asRNA is regulating gene expression. asRNAs may also be produced synthetically and have found wide spread use as research tools for gene knockdown. They may also have therapeutic applications.

<span class="mw-page-title-main">Silencer (genetics)</span> Type of DNA sequence

In genetics, a silencer is a DNA sequence capable of binding transcription regulation factors, called repressors. DNA contains genes and provides the template to produce messenger RNA (mRNA). That mRNA is then translated into proteins. When a repressor protein binds to the silencer region of DNA, RNA polymerase is prevented from transcribing the DNA sequence into RNA. With transcription blocked, the translation of RNA into proteins is impossible. Thus, silencers prevent genes from being expressed as proteins.

<span class="mw-page-title-main">Regulator gene</span>

A regulator gene, regulator, or regulatory gene is a gene involved in controlling the expression of one or more other genes. Regulatory sequences, which encode regulatory genes, are often at the five prime end (5') to the start site of transcription of the gene they regulate. In addition, these sequences can also be found at the three prime end (3') to the transcription start site. In both cases, whether the regulatory sequence occurs before (5') or after (3') the gene it regulates, the sequence is often many kilobases away from the transcription start site. A regulator gene may encode a protein, or it may work at the level of RNA, as in the case of genes encoding microRNAs. An example of a regulator gene is a gene that codes for a repressor protein that inhibits the activity of an operator.

Cis-regulatory elements (CREs) or Cis-regulatory modules (CRMs) are regions of non-coding DNA which regulate the transcription of neighboring genes. CREs are vital components of genetic regulatory networks, which in turn control morphogenesis, the development of anatomy, and other aspects of embryonic development, studied in evolutionary developmental biology.

<span class="mw-page-title-main">CCAAT-enhancer-binding proteins</span> Protein family

CCAAT-enhancer-binding proteins is a family of transcription factors composed of six members, named from C/EBPα to C/EBPζ. They promote the expression of certain genes through interaction with their promoters. Once bound to DNA, C/EBPs can recruit so-called co-activators that in turn can open up chromatin structure or recruit basal transcription factors.

In the field of molecular biology, trans-acting, in general, means "acting from a different molecule". It may be considered the opposite of cis-acting, which, in general, means "acting from the same molecule".

<span class="mw-page-title-main">Eukaryotic transcription</span> Transcription is heterocatalytic function of DNA

Eukaryotic transcription is the elaborate process that eukaryotic cells use to copy genetic information stored in DNA into units of transportable complementary RNA replica. Gene transcription occurs in both eukaryotic and prokaryotic cells. Unlike prokaryotic RNA polymerase that initiates the transcription of all different types of RNA, RNA polymerase in eukaryotes comes in three variations, each translating a different type of gene. A eukaryotic cell has a nucleus that separates the processes of transcription and translation. Eukaryotic transcription occurs within the nucleus where DNA is packaged into nucleosomes and higher order chromatin structures. The complexity of the eukaryotic genome necessitates a great variety and complexity of gene expression control.

Post-transcriptional regulation is the control of gene expression at the RNA level. It occurs once the RNA polymerase has been attached to the gene's promoter and is synthesizing the nucleotide sequence. Therefore, as the name indicates, it occurs between the transcription phase and the translation phase of gene expression. These controls are critical for the regulation of many genes across human tissues. It also plays a big role in cell physiology, being implicated in pathologies such as cancer and neurodegenerative diseases.

The Magnesium responsive RNA element, not to be confused with the completely distinct M-box riboswitch, is a cis-regulatory element that regulates the expression of the magnesium transporter protein MgtA. It is located in the 5' UTR of this gene. The mechanism for the potential magnesium-sensing capacity of this RNA is still unclear, though a recent report suggests that the RNA element targets the mgtA transcript for degradation by RNase E when cells are grown in high Mg2+ environments.

References

  1. 1 2 3 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. 1 2 3 4 5 6 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. 1 2 3 4 5 6 7 8 9 10 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. 1 2 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. 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.