The initiator element (''Inr''), sometimes referred to as initiator motif, is a

core promoter 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 ...

that is similar in function to the Pribnow box (in

prokaryotes A prokaryote () is a single-celled organism that lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek πρό (, 'before') and κάρυον (, 'nut' or 'kernel').Campbell, N. "Biology:Concepts & Con ...

) or the

TATA box In molecular biology, the TATA box (also called the Goldberg–Hogness 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 ...

(in

eukaryotes Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacter ...

). The ''Inr'' is the simplest functional promoter that is able to direct transcription initiation without a functional TATA box. It has the

consensus sequence In molecular biology and bioinformatics, the consensus sequence (or canonical sequence) is the calculated order of most frequent residues, either nucleotide or amino acid, found at each position in a sequence alignment. It serves as a simplified r ...

YYANWYY in humans. Similarly to the TATA box, the Inr element facilitates the binding of

transcription Factor II D 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 o ...

(

TFIID 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 o ...

). The Inr works by enhancing binding affinity and strengthening the promoter.

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 David Baltimore (born March 7, 1938) is an American biologist, university administrator, and 1975 Nobel laureate in Physiology or Medicine. He is President Emeritus and Distinguished Professor of Biology at the California Institute of Tec ...

in 1989. 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 RNA polymerase II (RNAP II and Pol II) is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNAP enzymes found in the nucleus of euka ...

. A gene with both types of promoters will have higher promoter binding strength, easier activation and higher levels of transcription activity. The

, which is a component of the

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. 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. 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

Location

The Inr element sequence is located -6 bp upstream of the transcription start site and continues to around +45 bp downstream. 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.

Sequence

The

of Inr in humans was inferred to be YYANWYY. The consensus sequence in

Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...

is TCAKTY.

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. Although Inr element varies between promoters, the sequence is highly conserved between humans and yeast. 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 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. A replacement of the

Adenosine Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9- glycosidic bond. Adenosine is one of the four nucleoside building ...

nucleotide at the +1 to G or T changes transcription activity by 10% and a replacement of

Thymine Thymine () ( symbol T or Thy) is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidin ...

at the +3 position changes transcription activity levels by 22%.

Significance

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

References

2. {{Transcription DNA Regulatory sequences