E-box

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An E-box (enhancer box) is a DNA response element found in some eukaryotes that acts as a protein-binding site and has been found to regulate gene expression in neurons, muscles, and other tissues. [1] Its specific DNA sequence, CANNTG (where N can be any nucleotide), with a palindromic canonical sequence of CACGTG, [2] is recognized and bound by transcription factors to initiate gene transcription. Once the transcription factors bind to the promoters through the E-box, other enzymes can bind to the promoter and facilitate transcription from DNA to mRNA.

Contents

Discovery

The E-box was discovered in a collaboration between Susumu Tonegawa's and Walter Gilbert's laboratories in 1985 as a control element in immunoglobulin heavy-chain enhancer. [3] [4] They found that a region of 140 base pairs in the tissue-specific transcriptional enhancer element was sufficient for different levels of transcription enhancement in different tissues and sequences. They suggested that proteins made by specific tissues acted on these enhancers to activate sets of genes during cell differentiation.

In 1989, David Baltimore's lab discovered the first two E-box binding proteins, E12 and E47. [5] These immunoglobulin enhancers could bind as heterodimers to proteins through bHLH domains. In 1990, another E-protein, ITF-2A (later renamed E2-2Alt) was discovered that can bind to immunoglobulin light chain enhancers. [6] Two years later, the third E-box binding protein, HEB, was discovered by screening a cDNA library from HeLa cells. [7] A splice-variant of the E2-2 was discovered in 1997 and was found to inhibit the promoter of a muscle-specific gene. [8]

Since then, researchers have established that the E-box affects gene transcription in several eukaryotes and found E-box binding factors that identify E-box consensus sequences. [9] In particular, several experiments have shown that the E-box is an integral part of the transcription-translation feedback loop that comprises the circadian clock.

Binding

E-box binding proteins play a major role in regulating transcriptional activity. These proteins usually contain the basic helix-loop-helix protein structural motif, which allows them to bind as dimers. [10] This motif consists of two amphipathic α-helices, separated by a small sequence of amino acids, that form one or more β-turns. The hydrophobic interactions between these α-helices stabilize dimerization. Besides, each bHLH monomer has a basic region, which helps mediate recognition between the bHLH monomer and the E-box (the basic region interacts with the major groove of the DNA). Depending on the DNA motif ("CAGCTG" versus "CACGTG") the bHLH protein has a different set of basic residues.

Relative Position of CTRR and E-Box CTRR and Ebox.png
Relative Position of CTRR and E-Box

The E-box binding is modulated by Zn2+ in mice. The CT-Rich Regions (CTRR) located about 23 nucleotides upstream of the E-box is important in E-box binding, transactivation (increased rate of genetic expression), and transcription of circadian genes BMAL1/NPAS2 and BMAL1/CLOCK complexes. [11]

The binding specificity of different E-boxes is found to be essential in their function. E-boxes with different functions have a different number and type of binding factor. [12]

The consensus sequence of the E-box is usually CANNTG; however, there exist other E-boxes of similar sequences called noncanonical E-boxes. These include, but are not limited to:

Role in the circadian clock

The link between E-box-regulated genes and the circadian clock was discovered in 1997, when Hao, Allen, and Hardin (Department of Biology at Texas A&M University) analyzed rhythmicity in the period (per) gene in Drosophila melanogaster . [16] They found a circadian transcriptional enhancer upstream of the per gene within a 69 bp DNA fragment. Depending upon PER protein levels, the enhancer drove high levels of mRNA transcription in both LD (light-dark) and DD (constant darkness) conditions. The enhancer was found to be necessary for high-level gene expression but not for circadian rhythmicity. It also works independently as a target of the BMAL1/CLOCK complex.

The E-box plays an important role in circadian genes; so far, nine E/E'BOX controlled circadian genes have been identified: PER1, PER2, BHLHB2, BHLHB3, CRY1, DBP, Nr1d1, Nr1d2, and RORC. [17] As the E-box is connected to several circadian genes, it is possible that the genes and proteins associated with it are "crucial and vulnerable points in the (circadian) system." [18]

The E-box is one of the top five transcription factor families associated with the circadian phase and is found in most tissues. [19] A total of 320 E-box-controlled genes are found in the SCN (suprachiasmatic nucleus), liver, aorta, adrenal, WAT (white adipose tissue), brain, atria, ventricle, prefrontal cortex, skeletal muscle, BAT (brown adipose tissue), and calvarial bone.

E-box like CLOCK-related elements (EL-box; GGCACGAGGC) are also important in maintaining circadian rhythmicity in clock-controlled genes. Similarly to the E-box, the E-box like CLOCK related element can also induce transcription of BMAL1/CLOCK, which can then lead to expression in other EL-box containing genes (Ank, DBP, Nr1d1). [20] However, there are differences between the EL-box and the regular E-box. Suppressing DEC1 and DEC2 has a stronger effect on E-box than on EL-box. Furthermore, HES1, which can bind to a different consensus sequence (CACNAG, known as the N-box), shows suppression effect in EL-box, but not in E-box.

Both non-canonical E-boxes and E-box-like sequences are crucial for circadian oscillation. Recent research on this forms an hypothesis that either a canonical or non-canonical E-box followed by an E-box like sequence with 6 base pair interval in between is a necessary combination for circadian transcription. [21] In silico analysis also suggests that such an interval existed in other known clock-controlled genes.


Role of proteins which bind to E-boxes

There are several proteins that bind to the E-box and affect gene transcription.

CLOCK-ARNTL complex

The CLOCK-ARNTL (BMAL1) complex is an integral part of the mammalian circadian cycle and vital in maintaining circadian rhythmicity.

Knowing that binding activates transcription of the per gene in the promoter region, researchers discovered in 2002 that DEC1 and DEC2 (bHLH transcription factors) repressed the CLOCK-BMAL1 complex through direct interaction with BMAL1 and/or competition for E-box elements. They concluded that DEC1 and DEC2 were regulators of the mammalian molecular clock. [22]

In 2006, Ripperger and Schibler discovered that the binding of this complex to the E-box drove circadian DBP transcription and chromatin transitions (a change from chromatin to facultative heterochromatin). [23] It was concluded that CLOCK regulates DBP expression by binding to E-box motifs in enhancer regions located in the first and second introns.

MYC (c-Myc, an oncogene)

MYC (c-Myc), a gene that codes for a transcription factor Myc, is important in regulating mammalian cell proliferation and apoptosis.

In 1991, researchers tested whether c-Myc could bind to DNA by dimerizing it to E12. Dimers of E6, the chimeric protein, were able to bind to an E-box element (GGCCACGTGACC) which was recognized by other HLH proteins. [24] Expression of E6 suppressed the function of c-Myc, which showed a link between the two.

In 1996, it was found that Myc heterodimerizes with MAX and that this heterodimeric complex could bind to the CAC(G/A)TG E-box sequence and activate transcription. [25]

In 1998, it was concluded that the function of c-Myc depends upon activating transcription of particular genes through E-box elements. [26]

MYOD1 (MyoD)

MyoD comes from the Mrf bHLH family and its main role is myogenesis, the formation of muscular tissue. [9] Other members in this family include myogenin, Myf5, Myf6, Mist1, and Nex-1.

When MyoD binds to the E-box motif CANNTG, muscle differentiation and expression of muscle-specific proteins is initiated. [27] The researchers ablated various parts of the recombinant MyoD sequence and concluded that MyoD used encompassing elements to bind the E-box and the tetralplex structure of the promoter sequence of the muscle specific gene α7 integrin and sarcomeric sMtCK.

MyoD regulates HB-EGF (Heparin-binding EGF-like growth factor), a member of the EGF (Epidermal growth factor) family that stimulates cell growth and proliferation. [9] It plays a role in the development of hepatocellular carcinoma, prostate cancer, breast cancer, esophageal cancer, and gastric cancer.

MyoD can also bind to noncanonical E boxes of MyoG and regulate its expression. [28]

MyoG (Myogenin)

MyoG belongs to the MyoD transcription factor family. MyoG-E-Box binding is necessary for neuromuscular synapse formation as an HDAC-Dach2-myogenin signaling pathway in skeletal muscle gene expression has been identified. [29] Decreased MyoG expression has been shown in patients with muscle wasting symptom. [30]

MyoG and MyoD have also been shown to involve in myoblast differentiation. [31] They act by transactivating cathepsin B promotor activity and inducing its mRNA expression.

TCF3 (E47)

E47 is produced by alternative spliced E2A in E47 specific bHLH-encoding exons. Its role is to regulate tissue specific gene expression and differentiation. Many kinases have been associated with E47 including 3pk and MK2. These 2 proteins form a complex with E47 and reduce its transcription activity. [32] CKII and PKA are also shown to phosphorylate E47 in vitro. [33] [34] [35]

Similar to other E-box binding proteins, E47 also binds to the CANNTG sequence in the E-box. In homozygous E2A knock-out mice, B cells development stops before the DJ arrangement stage and the B cells fail to mature. [36] E47 has been shown to bind either as heterodimer(with E12) [37] or as homodimer(but weaker). [38]

Recent research

Although the structural basis for how BMAL1/CLOCK interact with the E-box is unknown, recent research has shown that the bHLH protein domains of BMAL1/CLOCK are highly similar to other bHLH containing proteins, e.g. Myc/Max, which have been crystallized with E-boxes. [39] It is surmised that specific bases are necessary to support this high affinity binding. Furthermore, the sequence constraints on the region around the circadian E-box are not fully understood: it is believed to be necessary but not sufficient for E-boxes to be randomly spaced from each other in the genetic sequence in order for circadian transcription to occur. Recent research involving the E-box has been aimed at trying to find more binding proteins as well as discovering more mechanisms for inhibiting binding.

Researchers at the Medical School of Nanjing University found that the amplitude of FBXL3 (F-box/Leucine rich-repeat protein) is expressed via an E-box. [40] They studied mice with FBXL3 deficiency and found that it regulates feedback loops in circadian rhythms by affecting circadian period length.

A study published April 4, 2013 by researchers at Harvard Medical School found that the nucleotides on either side of an E-box influences which transcription factors can bind to the E-box itself. [41] These nucleotides determine the 3-D spatial arrangement of the DNA strand and restrict the size of binding transcription factors. The study also found differences in binding patterns between in vivo and in vitro strands.

Related Research Articles

<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">MyoD</span> Mammalian protein found in Homo sapiens

MyoD, also known as myoblast determination protein 1, is a protein in animals that plays a major role in regulating muscle differentiation. MyoD, which was discovered in the laboratory of Harold M. Weintraub, belongs to a family of proteins known as myogenic regulatory factors (MRFs). These bHLH transcription factors act sequentially in myogenic differentiation. Vertebrate MRF family members include MyoD1, Myf5, myogenin, and MRF4 (Myf6). In non-vertebrate animals, a single MyoD protein is typically found.

<span class="mw-page-title-main">Basic helix–loop–helix</span> Protein structural motif

A basic helix–loop–helix (bHLH) is a protein structural motif that characterizes one of the largest families of dimerizing transcription factors. The word "basic" does not refer to complexity but to the chemistry of the motif because transcription factors in general contain basic amino acid residues in order to facilitate DNA binding.

<span class="mw-page-title-main">Leucine zipper</span> DNA-binding structural motif

A leucine zipper is a common three-dimensional structural motif in proteins. They were first described by Landschulz and collaborators in 1988 when they found that an enhancer binding protein had a very characteristic 30-amino acid segment and the display of these amino acid sequences on an idealized alpha helix revealed a periodic repetition of leucine residues at every seventh position over a distance covering eight helical turns. The polypeptide segments containing these periodic arrays of leucine residues were proposed to exist in an alpha-helical conformation and the leucine side chains from one alpha helix interdigitate with those from the alpha helix of a second polypeptide, facilitating dimerization.

<span class="mw-page-title-main">Myogenin</span> Mammalian protein found in Homo sapiens

Myogenin, is a transcriptional activator encoded by the MYOG gene. Myogenin is a muscle-specific basic-helix-loop-helix (bHLH) transcription factor involved in the coordination of skeletal muscle development or myogenesis and repair. Myogenin is a member of the MyoD family of transcription factors, which also includes MyoD, Myf5, and MRF4.

The scleraxis protein is a member of the basic helix-loop-helix (bHLH) superfamily of transcription factors. Currently two genes have been identified to code for identical scleraxis proteins.

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

CLOCK is a gene encoding a basic helix-loop-helix-PAS transcription factor that is known to affect both the persistence and period of circadian rhythms.

Myogenic regulatory factors (MRF) are basic helix-loop-helix (bHLH) transcription factors that regulate myogenesis: MyoD, Myf5, myogenin, and MRF4.

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

MYC proto-oncogene, bHLH transcription factor is a protein that in humans is encoded by the MYC gene which is a member of the myc family of transcription factors. The protein contains basic helix-loop-helix (bHLH) structural motif.

<span class="mw-page-title-main">NPAS2</span> Protein-coding gene in the species Homo sapiens

Neuronal PAS domain protein 2 (NPAS2) also known as member of PAS protein 4 (MOP4) is a transcription factor protein that in humans is encoded by the NPAS2 gene. NPAS2 is paralogous to CLOCK, and both are key proteins involved in the maintenance of circadian rhythms in mammals. In the brain, NPAS2 functions as a generator and maintainer of mammalian circadian rhythms. More specifically, NPAS2 is an activator of transcription and translation of core clock and clock-controlled genes through its role in a negative feedback loop in the suprachiasmatic nucleus (SCN), the brain region responsible for the control of circadian rhythms.

<span class="mw-page-title-main">FBXL3</span> Protein-coding gene in the species Homo sapiens

FBXL3 is a gene in humans and mice that encodes the F-box/LRR-repeat protein 3 (FBXL3). FBXL3 is a member of the F-box protein family, which constitutes one of the four subunits in the SCF ubiquitin ligase complex.

<span class="mw-page-title-main">ARNTL2</span> Protein-coding gene in humans

Aryl hydrocarbon receptor nuclear translocator-like 2, also known as Arntl2, Mop9, Bmal2, or Clif, is a gene.

<span class="mw-page-title-main">TCF3</span> Protein-coding gene in the species Homo sapiens

Transcription factor 3, also known as TCF3, is a protein that in humans is encoded by the TCF3 gene. TCF3 has been shown to directly enhance Hes1 expression.

<span class="mw-page-title-main">Myocyte-specific enhancer factor 2A</span> Protein-coding gene in the species Homo sapiens

Myocyte-specific enhancer factor 2A is a protein that in humans is encoded by the MEF2A gene. MEF2A is a transcription factor in the Mef2 family. In humans it is located on chromosome 15q26. Certain mutations in MEF2A cause an autosomal dominant form of coronary artery disease and myocardial infarction.

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

MAX is a gene that in humans encodes the MAX transcription factor.

<span class="mw-page-title-main">HES1</span> Protein-coding gene in the species Homo sapiens

Transcription factor HES1 is a protein that is encoded by the Hes1 gene, and is the mammalian homolog of the hairy gene in Drosophila. HES1 is one of the seven members of the Hes gene family (HES1-7). Hes genes code nuclear proteins that suppress transcription.

<span class="mw-page-title-main">BHLHE41</span> Protein-coding gene in humans

"Basic helix-loop-helix family, member e41", or BHLHE41, is a gene that encodes a basic helix-loop-helix transcription factor repressor protein in various tissues of both humans and mice. It is also known as DEC2, hDEC2, and SHARP1, and was previously known as "basic helix-loop-helix domain containing, class B, 3", or BHLHB3. BHLHE41 is known for its role in the circadian molecular mechanisms that influence sleep quantity as well as its role in immune function and the maturation of T helper type 2 cell lineages associated with humoral immunity.

<span class="mw-page-title-main">Basic helix-loop-helix ARNT-like protein 1</span> Protein-coding gene in the species Homo sapiens

Basic helix-loop-helix ARNT-like protein 1 or aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL), or brain and muscle ARNT-like 1 is a protein that in humans is encoded by the BMAL1 gene on chromosome 11, region p15.3. It's also known as MOP3, and, less commonly, bHLHe5, BMAL, BMAL1C, JAP3, PASD3, and TIC.

Transcription-translation feedback loop (TTFL) is a cellular model for explaining circadian rhythms in behavior and physiology. Widely conserved across species, the TTFL is auto-regulatory, in which transcription of clock genes is regulated by their own protein products.

dClock (clk) is a gene located on the 3L chromosome of Drosophila melanogaster. Mapping and cloning of the gene indicates that it is the Drosophila homolog of the mouse gene CLOCK (mClock). The Jrk mutation disrupts the transcription cycling of per and tim and manifests dominant effects.

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