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In 1989, researchers discovered the first two E-box binding [[proteins]], E12 and E47<ref>Murre C, Mc Caw P S, Vaessin H, Caudy M, Jan L Y, Cabrera C V, Buskin J N, Hauschka S D, Lassar A B, Weintraub H, et al. Cell. 1989 Aug;58(3):537–544.</ref>. These [[immunoglobulin]] enhancers could bind to [[proteins]] with [[bHLH]] domains as heterodimers. In 1990, other researchers discovered another E-protein, ITF-2A (later renamed E2-2Alt) that was able to bind to [[immunoglobulin]] light-chain enhancers. <ref>Henthorn P, Kiledjian M, Kadesch T. Science. 1990;247(4941):467–470.</ref> . Two years later, the third E-box binding protein, HEB, was discovered by screening a [[cDNA]] library from [[HeLa]] cells <ref>Hu S-J, Olson E N, Kingston R E. HEB, ''Mol Cell Biol''. 1992;12(3):1031–1042.</ref>. A splice-variant of the E2-2 was discovered in 1997 and was found to inhibit the [[promoter (genetics)|promoter]] of a muscle-specific [[gene]] <ref>Chen B, Lim R W. ''J Biol Chem''. 1997 Jan:272(4):2459-2463.</ref>.
In 1989, researchers discovered the first two E-box binding [[proteins]], E12 and E47<ref>Murre C, Mc Caw P S, Vaessin H, Caudy M, Jan L Y, Cabrera C V, Buskin J N, Hauschka S D, Lassar A B, Weintraub H, et al. Cell. 1989 Aug;58(3):537–544.</ref>. These [[immunoglobulin]] enhancers could bind to [[proteins]] with [[bHLH]] domains as heterodimers. In 1990, other researchers discovered another E-protein, ITF-2A (later renamed E2-2Alt) that was able to bind to [[immunoglobulin]] light-chain enhancers. <ref>Henthorn P, Kiledjian M, Kadesch T. Science. 1990;247(4941):467–470.</ref> . Two years later, the third E-box binding protein, HEB, was discovered by screening a [[cDNA]] library from [[HeLa]] cells <ref>Hu S-J, Olson E N, Kingston R E. HEB, ''Mol Cell Biol''. 1992;12(3):1031–1042.</ref>. A splice-variant of the E2-2 was discovered in 1997 and was found to inhibit the [[promoter (genetics)|promoter]] of a muscle-specific [[gene]] <ref>Chen B, Lim R W. ''J Biol Chem''. 1997 Jan:272(4):2459-2463.</ref>.


⚫
Since then, researchers have found that the E-box affects gene [[transcription (genetics)|transcription]] in many genes and found several E-box binding factors, transcription factors that identify E-box [[consensus sequences]] <ref>Mädge B.: E-Box. In: Schwab M. (Ed.) Encyclopedia of Cancer: SpringerReference (www.springerreference.com). Springer-Verlag Berlin Heidelberg, 2009. DOI: 10.1007/SpringerReference_173452</ref>. 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]].
⚫
Also in 1997, Hao, Allen, and Hardin (Department of Biology in [[Texas A&M University]]) found that the E-box regulated [[gene expression]] in the [[circadian clock]] while analyzing rhythmicity in the period ([[per]]) gene in [[Drosophila melanogaster]]<ref>Hao H, Allen D L, Hardin P E. ''Mol Cell Biol''. 1997 Jul;17(7):3687-3693.</ref>. Within a 69 bp [[DNA]] fragment, the researchers found a circadian transcriptional enhancer upstream of the [[per]] gene. Dependent upon [[PER]] [[protein]], this [[enhancer (genetics)|enhancer]] drove high-amplitude [[mRNA]] cycling in both LD (light-dark) or DD (constant darkness) conditions and was found to be necessary for high-level [[gene expression]] but not for rhythmicity.

⚫
Since then, researchers have found that the E-box affects gene [[transcription (genetics)|transcription]] in many genes and found several E-box binding factors, which are transcription factors that identify E-box [[consensus sequences]] <ref>Mädge B.: E-Box. In: Schwab M. (Ed.) Encyclopedia of Cancer: SpringerReference (www.springerreference.com). Springer-Verlag Berlin Heidelberg, 2009. DOI: 10.1007/SpringerReference_173452</ref>. 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]].


==E-Box Binding==
==E-Box Binding==
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* CAGCTT E-Box found within MyoD core enhancer<ref>Zhang X., Patel S. P., McCarthy J. J., Rabchevsky A. G., Goldhamer D. J., Esser K. A. (2012)Nucleic Acids Res. 40, 3419–3430</ref>
* CAGCTT E-Box found within MyoD core enhancer<ref>Zhang X., Patel S. P., McCarthy J. J., Rabchevsky A. G., Goldhamer D. J., Esser K. A. (2012)Nucleic Acids Res. 40, 3419–3430</ref>
* CACCTCGTGAC sequence in the proximal promoter region of human and rat APOE<ref>Salero Enrique, Giménez Cecilio, Zafra Francisco. Biochem J. 2003 Mar 15;370(Pt 3):979–986.</ref>.
* CACCTCGTGAC sequence in the proximal promoter region of human and rat APOE<ref>Salero Enrique, Giménez Cecilio, Zafra Francisco. Biochem J. 2003 Mar 15;370(Pt 3):979–986.</ref>.

==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 in [[Texas A&M University]]) analyzed rhythmicity in the period ([[per]]) gene in [[Drosophila melanogaster]]<ref>Hao H, Allen D L, Hardin P E. ''Mol Cell Biol''. 1997 Jul;17(7):3687-3693.</ref>. Within a 69 bp [[DNA]] fragment, the researchers found a circadian transcriptional enhancer upstream of the [[per]] gene. Dependent upon [[PER]] [[protein]], this [[enhancer (genetics)|enhancer]] drove high-amplitude [[mRNA]] cycling in both LD (light-dark) or DD (constant darkness) conditions and was found to be necessary for high-level [[gene expression]] but not for rhythmicity. This was discovered independently as a target of the [[BMAL1]]/[[CLOCK]] complex.

The E-Box plays an important role in circadian [[genes]]; after the first discovery, nine E/E’BOX controlled circadian genes have been identified: [[PER1]], [[PER2]], [[BHLHB2]], [[BHLHB3]], [[CRY1]], Dbp, Nr1d1, Nr1d2, and Rorc<ref>{{cite journal|last=Panda|first=S|coauthors=Antoch MP, Miller BH, Su AI, Schook AB, Straume M, Schultz PG, Kay SA, Takahashi JS, Hogenesch JB|title=Coordinated transcription of key pathways in the mouse by the circadian clock|journal=Cell|year=2002|month=May|volume=109|issue=3|pages=307-320|pmid=12015981}}</ref>. As the E-box is connected to the most circadian genes, it is possible that [[genes]] and [[proteins]] associated with it are "crucial and vulnerable points in the system."<ref>{{cite journal|last=Herzog|first=Erik|title=Neurons and networks in daily rhythms|journal=Nature Reviews Neuroscience|year=2007|month=October|volume=8|pages=790-802|doi=10.1038/nrn2215}}</ref>

[[File:Nrn2215-f4.jpg|thumbnail|Role of the E-box in Circadian Controlled Genes Network]]

Furthermore, it controls genes across several tissues. Experiments that tested the link between [[transcription factor]] regulation and the gene’s circadian oscillation found that the EBOX was one of the top five transcription factor family and associated with the circadian phase in most tissues<ref>{{cite journal|last=Yan|first=Jun|coauthors=Haifang Wang, Yuting Liu, Chunxuan Shao|title=Analysis of Gene Regulatory Networks in the Mammalian Circadian Rhythm|journal=PLoS Computation Biology|year=2008|month=October|volume=4|issue=10|doi=10.1371/journal.pcbi.1000193}}</ref>. At CT 12 (circadian time 12), it was associated with CT12 in the majority of tissues including SCN ([[suprachiasmatic nucleus]]), [[liver]], [[aorta]], [[adrenal]], WAT ([[white adipose tissue]]), [[brain]], [[atria]], [[ventricle]] and [[prefrontal cortex]]. In CT10 (circadian time 10), it was associated with the [[skeletal muscle]], BAT ([[brown adipose tissue]]), and calvarial bone. This experiment attempted to identify the direct target genes of transcription factors in knockout or mutant experiments and found 320 EBOX controlled genes.

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 could then induce expression in other EL-box containing genes (Ank, Dbp, Nr1d1) <ref>{{cite journal|last=Ueshima|first=T|coauthors=Kawamoto T, Honda KK, Noshiro M, Fujimoto K, Nakao S, Ichinose N, Hashimoto S, Gotoh O, Kato Y|title=Identification of a new clock-related element EL-box involved in circadian regulation by BMAL1/CLOCK and HES1.|journal=Gene|year=2012|month=December|volume=510|issue=2|pages=118-125|pmid=22960268}}</ref>. The EL-box differs from the E-box as suppressing [[DEC1]] and DEC2 had a greater effect on the E-box than the EL-box and [[HES1]] suppressed activity in the EL-box but not the E-box. The researchers concluded that the EL-box element also contributes to circadian regulation of clock-controlled genes.

Both non-canonical E-boxes and E-box-like sequences are necessary for circadian oscillation. Recent research on this hypothesizes that a short 6 [[base pair]] interval between a canonical or non-canonical E-box and an E-box like sequences is necessary for circadian transcription<ref>{{cite journal|last=Nakahata|first=Y|coauthors=Yoshida M, Takano A, Soma H, Yamamoto T, Yasuda A, Nakatsu T, Takumi T|title=A direct repeat of E-box-like elements is required for cell-autonomous circadian rhythm of clock genes|journal=BMC Mol Biol|year=2008|month=January|volume=9|issue=1|doi=10.1186/1471-2199-9-1|pmid=18177499}}</ref> In silico analysis verified that such an interval existed in other known clock-controlled genes.


==Role of Proteins Which Bind to E-Boxes==
==Role of Proteins Which Bind to E-Boxes==

Revision as of 15:58, 22 April 2013

An E-box (Enhancer Box) is a DNA sequence which usually lies upstream of a gene in a promoter promoter region. It is a transcription factor binding site where the specific sequence of DNA, CANNTG (where N can be any nucleotide), is recognized by proteins that can bind to it to help initiate transcription of the gene. Once transcription factors bind to promoters, they allow for association of other enzymes which will transcribe the DNA into mRNA. The consensus sequence for the E-box element is CANNTG, with a palindromic canonical sequence of CACGTG [1]. Transcription factors containing the basic helix-loop-helix protein structural motif typically bind to E-boxes or related variant sequences and enhance transcription of the downstream gene.

Discovery

The E-box was discovered by George M. Church, Anne Ephrussi, Walter Gilbert, and Susumu Tonegawa in 1985 as a control element in immunoglobulin heavy-chain promoters promoter [2]. These researchers isolated nuclei from active immunoglobulin genes containing tissue-specific transcriptional enhancer elements. After treating the tissue culture cells with dimethyl sulfate and cleaving the cells with EcoRI, the scientists used gel electrophoresis to read the genomic sequence pattern. They began to ablate parts of the gene until reaching the conclusion that a region of 140 base pairs was sufficient for enhancement. Their results led them to conclude that other sequences (besides the consensus sequences) were necessary for enhancement and suggested that some element binds to the enhancer element “in a tissue and sequence specific fashion”; this supported their hypothesis that genes in distinct tissues made products that acted on enhancers to activate other genes (a feedback loop).

In 1989, researchers discovered the first two E-box binding proteins, E12 and E47[3]. These immunoglobulin enhancers could bind to proteins with bHLH domains as heterodimers. In 1990, other researchers discovered another E-protein, ITF-2A (later renamed E2-2Alt) that was able to bind to immunoglobulin light-chain enhancers. [4] . Two years later, the third E-box binding protein, HEB, was discovered by screening a cDNA library from HeLa cells [5]. A splice-variant of the E2-2 was discovered in 1997 and was found to inhibit the promoter of a muscle-specific gene [6].

Since then, researchers have found that the E-box affects gene transcription in many genes and found several E-box binding factors, transcription factors that identify E-box consensus sequences [7]. 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.

E-Box Binding

The HLH motif within the bHLH protein allows it to bind to the E-box as a dimer [8]. This motif includes two amphipathic α-helices, separated by a small sequence of amino acids, form one or more β-turn. The hydrophobic interactions between these α-helices stabilize dimerization; however, dimerization is necessary but not sufficient for DNA binding. 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 residue. Furthermore, the structure of the bHLH dimer bound to the DNA regulates the E-box and transcriptional activity.

Relative position of CTRR and Ebox, information comes from [1]

The binding of E-Box is found to be modulated by Zn2+ in mice. The CT-Rich Regions(CTRR) located about 23 nucleotides upstream of E-Box is found to be important in E-box binding, transactivation and circadian genes transcription of BMAL/NPAS2 and BMAL/CLOCK complexes[9] .

The binding specificity of different E-Boxes are essential to their function. The E-Boxes with different functions are found to have different number and type of binding factors[10].

As mentioned before, 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:

  • CACGTT sequence found to be 20 bp upstream of mouse Period2 (PER2) gene and regulate its expression[11]
  • CAGCTT E-Box found within MyoD core enhancer[12]
  • CACCTCGTGAC sequence in the proximal promoter region of human and rat APOE[13].

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 in Texas A&M University) analyzed rhythmicity in the period (per) gene in Drosophila melanogaster[14]. Within a 69 bp DNA fragment, the researchers found a circadian transcriptional enhancer upstream of the per gene. Dependent upon PER protein, this enhancer drove high-amplitude mRNA cycling in both LD (light-dark) or DD (constant darkness) conditions and was found to be necessary for high-level gene expression but not for rhythmicity. This was discovered independently as a target of the BMAL1/CLOCK complex.

The E-Box plays an important role in circadian genes; after the first discovery, nine E/E’BOX controlled circadian genes have been identified: PER1, PER2, BHLHB2, BHLHB3, CRY1, Dbp, Nr1d1, Nr1d2, and Rorc[15]. As the E-box is connected to the most circadian genes, it is possible that genes and proteins associated with it are "crucial and vulnerable points in the system."[16]

File:Nrn2215-f4.jpg
Role of the E-box in Circadian Controlled Genes Network

Furthermore, it controls genes across several tissues. Experiments that tested the link between transcription factor regulation and the gene’s circadian oscillation found that the EBOX was one of the top five transcription factor family and associated with the circadian phase in most tissues[17]. At CT 12 (circadian time 12), it was associated with CT12 in the majority of tissues including SCN (suprachiasmatic nucleus), liver, aorta, adrenal, WAT (white adipose tissue), brain, atria, ventricle and prefrontal cortex. In CT10 (circadian time 10), it was associated with the skeletal muscle, BAT (brown adipose tissue), and calvarial bone. This experiment attempted to identify the direct target genes of transcription factors in knockout or mutant experiments and found 320 EBOX controlled genes.

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 could then induce expression in other EL-box containing genes (Ank, Dbp, Nr1d1) [18]. The EL-box differs from the E-box as suppressing DEC1 and DEC2 had a greater effect on the E-box than the EL-box and HES1 suppressed activity in the EL-box but not the E-box. The researchers concluded that the EL-box element also contributes to circadian regulation of clock-controlled genes.

Both non-canonical E-boxes and E-box-like sequences are necessary for circadian oscillation. Recent research on this hypothesizes that a short 6 base pair interval between a canonical or non-canonical E-box and an E-box like sequences is necessary for circadian transcription[19] In silico analysis verified 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-BMAL1 complex:

The CLOCK-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, in 2002, researchers discovered that DEC1 and Dec2 (bHLH transcription factors) repressed the CLOCK-BMAL1 complex through direct interactions with Bmal1 and/or competition for E-box elements and concluded that Dec1 and Dec 2 were regulators of the mammalian molecular clock[20].

In 2006, Ripperger and Schibler discovered that the binding of this complex to the E-box drove circadian DBP transcription and chromatin transitions from chromatin that could undergo transcription to facultative heterochromatin[21]. It was concluded that CLOCK regulates Dbp expression by binding to E-box motifs in enhancer regions located in the first and second introns.

c-Myc (an oncogene):

c-Myc, a gene that codes for a transcription 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[22]. 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 transcription [23].

In 1998, it was concluded that the function of c-Myc depends upon activating transcription of particular genes through E-box elements[24].

Other genes that the E-box regulating protein c-Myc regulates include :

  • CAD (carbamoyl-phosphate synthase/aspartate carbamoyltransferase/dihydroorotase), an enzyme involved in synthesizing pyrimidine and is essential for cell growth
  • Cdc25A, an oncogene which codes for cdk activating phosphatase and plays a role in cell cycle progression
  • Cyclin B1, which activates cdc2 kinase. Overexpression is often a characteristic of cancer cell lines.
  • Ornithine decarboxylase is an enzyme integral in polyamine synthesis and vital for cell growth.
  • Prothymosin alpha is a protein related to cell growth
  • RCC1 (Regulator of chromosome condensation-1) is a guanine exchange factor required for cell proliferation
  • TERT (Telomerase reverse transcriptase) is a catalytic subunit of telomerase that maintains chromosome ends

MyoD

MyoD comes from the [[Mrf (myogenic regulatory factors}|Mrf]] bHLH family and its main role is myogenesis, the formation of muscular tissue[25]. Other members in this family include myogenin, Myf5, Myf6, Mist1, Mrf4, and Nex-1.

When MyoD binds to the E-box motif CANNTG, muscle differentiation and expression of muscle-specific proteins is initiated[26]. 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), which is a member of the EGF family[27]. It plays a role in the development of hepatocellular carcinoma, prostate cancer, breast cancer, esophageal cancer, and gastric cancer.

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

MyoG

MyoG belongs to the MyoD transcription factor family. MyoG-E-Box binding is necessary to neuromuscular synapse formation and a 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 transactivate cathepsin B promotor activity and induce it's mRNA expression.

E47

E47 is produced by alternative spliced E2A in E47 specific bHLH-encoding exons. It involves in regulation of tissue specific gene expression and differentiation. Many kinases have been identified for E47 including: 3pk and MK2. These 2 proteins form 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 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

The structural basis for how BMAL1/CLOCK interact with the E-box is unknown, but their bHLH domains are highly similar to other bHLH containing proteins, e.g. Myc/Max, which have been crystalized 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 understand: 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.

A recent study out of Uppsala University in Sweden implicated the AST2-RACK1 complex in inhibiting binding of the BMAL1-CLOCK complex to the E-box[40]. The researchers were studying the role of Astakine-2 in melatonin-induced circadian regulation, and, by studying crustaceans, they found that AST2 is necessary for inhibiting the binding of the BMAL1-CLOCK complex to the E-box. Further, they found that melatonin secretion is responsible for regulating AST2 expression, indicating that inhibiting binding to the E-box is fundamental to affecting the clock in any animal that has the AST2 molecule.

Another study by researchers at the Medical School of Nanjing University implicated FBXL3 (F-box/Leucine rich-repeat protein) in the amplitudes of genes expressed via an E-box[41]. The researchers studied mice that were deficient in the protein and found that FBXL3 regulated feedback loops in circadian rhythms by affecting circadian period length and "robustness of the clock."

A study published April 4, 2013 by researchers at Harvard Medical School found that the nucleotides on either side of an E-box influences what transcription factors can bind to the E-box itself[42]. These nucleotides determine the spatial arrangement of the DNA strand in 3-D, restricting the size of transcription factors able to bind to the E-box sequence. The study found differences in binding patters between in vivo and in vitro strands.

A topic gaining considerable attention in E-box-related research is the zinc finger E-box binding homeobox 1 (ZEB1). Research has shown that ZEB1 promotes metastasis in multiple types of cancer, so research in how to inhibit ZEB1 is a growing field of study.


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See also


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