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 YYA+1NWYY in humans. [a] [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 (TSS) of eukaryotic genes. It was originally described as a 17 bp element in 1989, [2] but other (newer and older) analyses have produced consensus sequences 2-9 bp in length. [3]

Inr in humans was first described in 1980 by Corden et al. as a broader TSS motif. It was first articulated and explained 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. [4] 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. [5] 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 [6]

Archaea have some conservation at the TSS that determines promoter efficiency, which makes it a kind of initiator element. There is however no identified homolog of TAF1/2, so it's unknown how the archaeal Inr works. [7]

Location and sequence

The Inr element encompasses, simply, the 2-9 bp around the transcription start site (+1) that usually follow a consensus sequence. The exact range of bases it encompasses varies by the choice of consensus. The original human consensus of 1980 was YYCA+1YYYYY. Through mutational analysis by Lo and Smale, the "functional" consensus sequence of Inr in humans was inferred to be YYA+1NWYY. [a] Human genome-wide CAGE data suggests a very simple consensus of YR+1. Vo ngoc et al. have characterized the Inr at focused core promoters (those with a single or a narrow cluster of start sites) and found BBCA+1BW. [3]

The consensus sequence in Drosophila is TCA+1KTY. [4]

The conserved consensus in archaea is YR+1. For Sulfolobus , the consensus for transcripts with 5' UTR of <4 nt is YR+1TG, while for the rest it's YR+1WMAAA. For the araS gene of Sulfolobus, the most functional sequence is G+1AGAMK. [7]

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. [8] Although Inr element varies between promoters, the sequence is highly conserved between humans and yeast. [8] 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 [9] 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. [8] 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%. [10]

Significance

The Inr element for core promoters was found to be more prevalent than the TATA box in eukaryotic promoter domains. [11] 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. [11] 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

  1. 1 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, W (Weak) stands for A/T (adenine or thymine, which both form only two hydrogen bonds), and K stands for G/T (Keto). Subscript +1 indicates the transcription start site.

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.

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">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.

<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 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.

Transcription factor TFIIA is a nuclear protein involved in the RNA polymerase II-dependent transcription of DNA. TFIIA is one of several general (basal) transcription factors (GTFs) that are required for all transcription events that use RNA polymerase II. Other GTFs include TFIID, a complex composed of the TATA binding protein TBP and TBP-associated factors (TAFs), as well as the factors TFIIB, TFIIE, TFIIF, and TFIIH. Together, these factors are responsible for promoter recognition and the formation of a transcription preinitiation complex (PIC) capable of initiating RNA synthesis from a DNA template.

<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

Transcription initiation factor TFIID subunit 7 also known as TAFII55 is a protein that in humans is encoded by the TAF7 gene.

<span class="mw-page-title-main">TAF1</span> Protein-coding gene in the species Homo sapiens

Transcription initiation factor TFIID subunit 1, also known as transcription initiation factor TFIID 250 kDa subunit (TAFII-250) or TBP-associated factor 250 kDa (p250), is a protein that in humans is encoded by the TAF1 gene.

<span class="mw-page-title-main">TAF4</span> Protein-coding gene in the species Homo sapiens

Transcription initiation factor TFIID subunit 4 is a protein that in humans is encoded by the TAF4 gene.

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

Transcription initiation factor TFIID subunit 2 is a protein that in humans is encoded by the TAF2 gene.

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

Transcription initiation factor TFIID subunit 9B is a protein that in humans is encoded by the TAF9B gene.

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.

<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>

The B recognition element (BRE) is a DNA sequence found in the promoter region of most genes in eukaryotes and Archaea. The BRE is a cis-regulatory element that is found immediately near TATA box, and consists of 7 nucleotides. There are two sets of BREs: one (BREu) found immediately upstream of the TATA box, with the consensus SSRCGCC; the other (BREd) found around 7 nucleotides downstream, with the consensus RTDKKKK.

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

In molecular biology, a downstream promoter element (DPE) is a core promoter element. Like all core promoters, the DPE plays an important role in the initiation of gene transcription by RNA polymerase II. The DPE was first described by T. W. Burke and James T. Kadonaga in Drosophila melanogaster at the University of California, San Diego in 1996. It is also present in other species including humans, but not Saccharomyces cerevisiae.

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

The TBP-associated factors (TAF) are proteins that associate with the TATA-binding protein in transcription initiation. It is a part of the transcription initiation factor TFIID multimeric protein complex. It also makes up many other factors, including SL1. They mediate the formation of the transcription preinitiation complex, a step preceding transcription of DNA to RNA by RNA polymerase II.

<span class="mw-page-title-main">Promoter activity</span>

Promoter activity is a term that encompasses several meanings around the process of gene expression from regulatory sequences —promoters and enhancers. Gene expression has been commonly characterized as a measure of how much, how fast, when and where this process happens. Promoters and enhancers are required for controlling where and when a specific gene is transcribed.

References

  1. 1 2 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 Vo Ngoc, L; Cassidy, CJ; Huang, CY; Duttke, SH; Kadonaga, JT (1 January 2017). "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. PMC   5287114 . PMID   28108474.
  4. 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.
  5. ↑ 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.
  6. ↑ 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.
  7. 1 2 Ao, X; Li, Y; Wang, F; Feng, M; Lin, Y; Zhao, S; Liang, Y; Peng, N (November 2013). "The Sulfolobus initiator element is an important contributor to promoter strength". Journal of bacteriology. 195 (22): 5216–22. doi:10.1128/JB.00768-13. PMID   24039266.
  8. 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.
  9. ↑ 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.
  10. ↑ 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.
  11. 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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