Initiator element

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The initiator element (Inr), sometimes referred to as initiator motif, is a core promoter that is similar in function to the Pribnow box (in prokaryotes) or the TATA box (in eukaryotes). The Inr is the simplest functional promoter that is able to direct transcription initiation without a functional TATA box. It has the consensus sequence YYANWYY in humans. [lower-alpha 1] [1] Similarly to the TATA box, the Inr element facilitates the binding of transcription Factor II D (TFIID). [1] The Inr works by enhancing binding affinity and strengthening the promoter.

Contents

Overview

The initiator element (Inr) is the most common sequence found at the transcription start site of eukaryotic genes. It is a 17 bp element. Inr in humans was first explained and sequenced by two MIT biologists, Stephen T. Smale and David Baltimore in 1989. [2] Their research showed that Inr promoter is able to initiate basal transcription in absence of the TATA box. In the presence of a TATA box or other promoters, the Inr increases the efficiency of transcription by working alongside the promoters to bind RNA polymerase II. A gene with both types of promoters will have higher promoter binding strength, easier activation and higher levels of transcription activity. The TFIID, which is a component of the RNA polymerase II preinitiation complex binds to both the TATA box and Inr. Two subunits, TAF1 and TAF2, of the TFIID recognize the Inr sequence and bring the complex together. [3] The interaction between TFIID and Inr is believed to be most imperative in initiating transcription. This is likey due to the Inr sequence overlapping the start site. [4] The Inr element is also believed to interact with activator Sp1, specificity protein 1 transcription factor. Sp1 is then able to regulate the activation and initiation of transcription [5]

Location

The Inr element sequence is located -6 bp upstream of the transcription start site and continues to around +45 bp downstream. [1] This sequence encompasses where the RNA polymerase will begin transcribing. The Inr element is located about ~20 bp downstream from the TATA box. The Inr region overlaps the transcription start site but the exact start and end positions are still being debated. [2]

Sequence

The consensus sequence of Inr in humans was inferred to be YYANWYY. [lower-alpha 2] [1] The consensus sequence in Drosophila is TCAKTY. [3]

Evolutionary change

Studies have shown that promoters with a functional Inr are more likely to lack a TATA box or to possess a degenerate TATA sequence. This is because a gene with an active Inr is less dependent on a functional TATA box or additional promoters. [6] Although Inr element varies between promoters, the sequence is highly conserved between humans and yeast. [6] An analysis of 7670 transcription start sites showed that roughly 40% had an exact match to the BBCA+1BW Inr sequence. While 16% contained only one mismatch [7] TFIID and subunits are very sensitive to the Inr sequence and nucleotide changes have been shown to drastically change the binding affinity. The +1 and -3 positions have been identified as the most critical for transcription efficiency and Inr function. [6] A replacement of the Adenosine nucleotide at the +1 to G or T changes transcription activity by 10% and a replacement of Thymine at the +3 position changes transcription activity levels by 22%. [8]

Significance

The Inr element for core promoters was found to be more prevalent than the TATA box in eukaryotic promoter domains. [9] In a study of 1800+ distinct human promoter sequences it was found that 49% contain the Inr element while 21.8% contain the TATA box. [9] Out of those sequences with the TATA box, 62% contained the Inr element as well. Though the Inr element is not fully understood it has been recognized as the most frequently occurring sequence at the start site of genes in multiple species. Further research can allow for more understanding of the elements that regulate gene production.

Notes

In nucleic acid notation for DNA, K stands for G/T (Keto)

  1. ↑ In nucleic acid notation for DNA, Y (pYrimidine) stands for C/T (cytosine or thymine, which are both pyrimidines), N (Nucleobase) is any of the four bases, and W (Weak) stands for A/T (adenine or thymine, which both form only two hydrogen bonds)
  2. ↑ In nucleic acid notation for DNA, Y (pYrimidine) stands for C/T (cytosine or thymine, which are both pyrimidines), N (Nucleobase) is any of the four bases, and W (Weak) stands for A/T (adenine or thymine, which both form only two hydrogen bonds)

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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.

The Pribnow box is a sequence of TATAAT of six nucleotides that is an essential part of a promoter site on DNA for transcription to occur in bacteria. It is an idealized or consensus sequence—that is, it shows the most frequently occurring base at each position in many promoters analyzed; individual promoters often vary from the consensus at one or more positions. It is also commonly called the -10 sequence, because it is centered roughly ten base pairs upstream from the site of initiation of transcription.

<span class="mw-page-title-main">Transcription preinitiation complex</span> Complex of proteins necessary for gene transcription in eukaryotes and archaea

The preinitiation complex is a complex of approximately 100 proteins that is necessary for the transcription of protein-coding genes in eukaryotes and archaea. The preinitiation complex positions RNA polymerase II at gene transcription start sites, denatures the DNA, and positions the DNA in the RNA polymerase II active site for transcription.

<span class="mw-page-title-main">General transcription factor</span> Class of protein transcription factors

General transcription factors (GTFs), also known as basal transcriptional factors, are a class of protein transcription factors that bind to specific sites (promoter) on DNA to activate transcription of genetic information from DNA to messenger RNA. GTFs, RNA polymerase, and the mediator constitute the basic transcriptional apparatus that first bind to the promoter, then start transcription. GTFs are also intimately involved in the process of gene regulation, and most are required for life.

<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.

In eukaryote cells, RNA polymerase III is a protein that transcribes DNA to synthesize 5S ribosomal RNA, tRNA and other small RNAs.

<span class="mw-page-title-main">TATA-binding protein</span> Protein-coding gene in the species Homo sapiens

The TATA-binding protein (TBP) is a general transcription factor that binds specifically to a DNA sequence called the TATA box. This DNA sequence is found about 30 base pairs upstream of the transcription start site in some eukaryotic gene promoters.

Transcription factor II D (TFIID) is one of several general transcription factors that make up the RNA polymerase II preinitiation complex. RNA polymerase II holoenzyme is a form of eukaryotic RNA polymerase II that is recruited to the promoters of protein-coding genes in living cells. It consists of RNA polymerase II, a subset of general transcription factors, and regulatory proteins known as SRB proteins. Before the start of transcription, the transcription Factor II D (TFIID) complex binds to the core promoter DNA of the gene through specific recognition of promoter sequence motifs, including the TATA box, Initiator, Downstream Promoter, Motif Ten, or Downstream Regulatory elements.

<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.

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<span class="mw-page-title-main">Transcription factor II B</span> Mammalian protein found in Homo sapiens

Transcription factor II B (TFIIB) is a general transcription factor that is involved in the formation of the RNA polymerase II preinitiation complex (PIC) and aids in stimulating transcription initiation. TFIIB is localised to the nucleus and provides a platform for PIC formation by binding and stabilising the DNA-TBP complex and by recruiting RNA polymerase II and other transcription factors. It is encoded by the TFIIB gene, and is homologous to archaeal transcription factor B and analogous to bacterial sigma factors.

<span class="mw-page-title-main">TAF7</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">TAF2</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">TAF9B</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">5′ flanking region</span>

The 5′ flanking region is a region of DNA that is adjacent to the 5′ end of the gene. The 5′ flanking region contains the promoter, and may contain enhancers or other protein binding sites. It is the region of DNA that is not transcribed into RNA. Not to be confused with the 5′ untranslated region, this region is not transcribed into RNA or translated into a functional protein. These regions primarily function in the regulation of gene transcription. 5′ flanking regions are categorized between prokaryotes and eukaryotes.

<span class="mw-page-title-main">B recognition element</span>

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<span class="mw-page-title-main">Downstream promoter element</span>

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<span class="mw-page-title-main">TBP-associated factor</span> Protein domains

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References

  1. 1 2 3 4 Xi, Hualin; Yong Yu; Yutao Fu; Jonathan Foley; Anason Halees; Zhiping Weng (June 2007). "Analysis of overrepresented motifs in human core promoters reveals dual regulatory roles of YY1". Genome Research. 17 (6): 798–806. doi:10.1101/gr.5754707. PMC   1891339 . PMID   17567998.
  2. 1 2 Smale, Stephen T.; Baltimore, David (1989-04-07). "The "initiator" as a transcription control element". Cell. 57 (1): 103–113. doi:10.1016/0092-8674(89)90176-1. ISSN   0092-8674. PMID   2467742. S2CID   33929615.
  3. 1 2 Lim, Chin Yan; Santoso, Buyung; Boulay, Thomas; Dong, Emily; Ohler, Uwe; Kadonaga, James T. (2004-07-01). "The MTE, a new core promoter element for transcription by RNA polymerase II". Genes & Development. 18 (13): 1606–1617. doi:10.1101/gad.1193404. ISSN   0890-9369. PMC   443522 . PMID   15231738.
  4. ↑ Kaufmann, J.; Smale, S. T. (1994-04-01). "Direct recognition of initiator elements by a component of the transcription factor IID complex". Genes & Development. 8 (7): 821–829. doi: 10.1101/gad.8.7.821 . ISSN   0890-9369. PMID   7926770.
  5. ↑ O'Shea-Greenfield, A.; Smale, S. T. (1992-01-15). "Roles of TATA and initiator elements in determining the start site location and direction of RNA polymerase II transcription". The Journal of Biological Chemistry. 267 (2): 1391–1402. doi: 10.1016/S0021-9258(18)48443-8 . ISSN   0021-9258. PMID   1730658.
  6. 1 2 3 Yang, Chuhu; Bolotin, Eugene; Jiang, Tao; Sladek, Frances M.; Martinez, Ernest (2007-03-01). "Prevalence of the Initiator over the TATA box in human and yeast genes and identification of DNA motifs enriched in human TATA-less core promoters". Gene. 389 (1): 52–65. doi:10.1016/j.gene.2006.09.029. ISSN   0378-1119. PMC   1955227 . PMID   17123746.
  7. ↑ Ngoc, Long Vo; Cassidy, California Jack; Huang, Cassidy Yunjing; Duttke, Sascha H. C.; Kadonaga, James T. (2017-01-20). "The human initiator is a distinct and abundant element that is precisely positioned in focused core promoters". Genes & Development. 31 (1): 6–11. doi:10.1101/gad.293837.116. ISSN   0890-9369. PMC   5287114 . PMID   28108474.
  8. ↑ Javahery, R; Khachi, A; Lo, K; Zenzie-Gregory, B; Smale, S T (1994-01-01). "DNA sequence requirements for transcriptional initiator activity in mammalian cells". Molecular and Cellular Biology. 14 (1): 116–127. doi:10.1128/mcb.14.1.116. ISSN   0270-7306. PMC   358362 . PMID   8264580.
  9. 1 2 Gershenzon, Naum I.; Ioshikhes, Ilya P. (2005-04-15). "Synergy of human Pol II core promoter elements revealed by statistical sequence analysis". Bioinformatics. 21 (8): 1295–1300. doi: 10.1093/bioinformatics/bti172 . ISSN   1367-4803. PMID   15572469.

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