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PubMed2006

A rare missense mutation in a type 2 diabetes patient decreases the transcriptional activity of human sterol regulatory element binding protein-1.

Sterol regulatory element binding protein 1 (SREBP-1) transcription factors play a key role in energy homeostasis by regulating genes involved in both carbohydrate and lipid metabolism, and in adipocyte differentiation. The 5' end of the mRNA-encoding SREBP-1 exists in two forms, designated 1a and 1c. The divergence results from the use of two transcription start sites that produce two separate 5' exons, each of which is spliced to a common exon 2. Mutations in the sterol regulatory element binding protein gene (SREBF)-1 may contribute to insulin resistance states. However, the variants described to date do not affect the SREBP function. In this study, we investigated the functional consequences of a novel missense mutation common to both SREBP-1 isoforms identified in a Spanish type 2 diabetic patient (c.677C>T, SREBP-1a p.T226M; c.605C>T, SREBP-1c p.T202M). Using reporter gene analysis and electrophoretic mobility shift assays, we found that this variant impairs the transcriptional activity and reduces DNA binding ability despite its comparable protein stability to the wild-type SREBP-1. This decreased activity impairs the expression of known downstream targets, such as the LDL receptor and fatty acid synthase genes. Our findings suggest that the threonine residue and/or surrounding region play an important role in the SREBP-1 function.

Animals↗

PubMed1998

Woodchuck hepatitis virus contains a tripartite posttranscriptional regulatory element.

The hepatitis B virus posttranscriptional regulatory element (HBVPRE) is a cis-acting RNA element that partially overlaps with enhancer I and is required for the cytoplasmic accumulation of HBV surface RNAs. We find that the closely related woodchuck hepatitis virus (WHV), which has been shown to lack a functional enhancer I, also contains a posttranscriptional regulatory element (WPRE). Deletion analysis suggests that the WPRE consists of three independent subelements. Comparison of the bipartite HBVPRE and tripartite WPRE activities reveals that the tripartite WPRE is two to three times more active than the bipartite HBVPRE. Mutation of a single WPRE subelement decreases WPRE activity to the level of the HBVPRE. Bipartite and tripartite chimeras of the WPRE and HBVPRE possess activities which suggest that elements containing three subelements are posttranscriptionally stronger than those containing two. These data demonstrate that the posttranscriptional regulatory element is conserved within the mammalian hepadnaviruses and that its strength is determined by the number of subelements within the RNA.

Amino Acid Sequence↗

PubMed1993

Deletional analysis of the human renin promoter: transcriptional activation by the SV40 enhancer enables identification of promoter regulatory elements in non-renin-expressing cells.

Identification of regulatory elements in the human renin gene promoter has been hindered by the lack of suitable renin-expressing cell lines. In this paper, the SV40 viral enhancer is coupled to a human renin promoter/chloramphenicol acetyltransferase (CAT) reporter gene construct, to determine whether promoter regulatory elements can be identified in the context of enhanced transcription in the normally non-renin-expressing HeLa cell line. The present results indicate that the SV40 enhancer can overcome tissue-specificity of the human renin promoter, and confer correctly initiated transcriptional activity to HeLa cells. Analysis of a series of 5'-end deletions of the human renin promoter linked to the CAT gene and SV40 enhancer identified negative regulatory elements between positions-275 and -225, and between-142 and -102 of the human renin promoter, as well as a positive regulatory element between -225 and -142. Thus, studies of renin promoter regulatory elements need not be limited to renin-expressing cells, but can be performed in non-renin-expressing cells with the addition of an enhancer. This strategy can be generally applicable to the study of tissue-specific gene regulation in cases where there are no specific cell lines available.

Chloramphenicol O-Acetyltransferase↗

PubMed1991

Different combinations of regulatory elements may explain why placenta-specific expression of the glycoprotein hormone alpha-subunit gene occurs only in primates and horses.

Expression of the glycoprotein hormone alpha-subunit gene occurs in the pituitary of all mammals but in placenta of only primates and horses. In humans, two different elements, termed upstream regulatory element (URE) and cAMP response element (CRE), are required for placenta-specific expression of the alpha-subunit gene. The URE binds a protein unique to placenta whereas the CRE binds a ubiquitous protein. Comparative analysis of the promoter-regulatory region of the alpha-subunit gene from a number of mammals indicates that a functional URE has been retained and suggests the potential for placenta-specific expression. Indirect evidence also indicates that the URE-binding protein has been conserved, even in placenta from mammals that fail to express the alpha-subunit gene. Lack of expression of the alpha-subunit gene in placenta of rodents and cattle can be traced to a single nucleotide change that renders the CRE-like sequence of these genes incapable of binding the protein that confers responsiveness to cAMP. In contrast, although expression of the alpha-subunit gene occurs in horse placenta, the promoter-regulatory region lacks a functional CRE but appears to retain a functional URE. This suggests that either a different accessory element and cognate protein interacts with the horse URE to provide placenta-specific expression or that a completely different set of regulatory elements is required for placenta-specific expression in horses.

Animals↗

PubMed2006

Adding sequence context to a Markov background model improves the identification of regulatory elements.

MOTIVATION: Many computational methods for identifying regulatory elements use a likelihood ratio between motif and background models. Often, the methods use a background model of independent bases. At least two different Markov background models have been proposed with the aim of increasing the accuracy of predicting regulatory elements. Both Markov background models suffer theoretical drawbacks, so this article develops a third, context-dependent Markov background model from fundamental statistical principles. RESULTS: Datasets containing known regulatory elements in eukaryotes provided a basis for comparing the predictive accuracies of the different background models. Non-parametric statistical tests indicated that Markov models of order 3 constituted a statistically significant improvement over the background model of independent bases. Our model performed slightly better than the previous Markov background models. We also found that for discriminating between the predictive accuracies of competing background models, the correlation coefficient is a more sensitive measure than the performance coefficient. AVAILABILITY: Our C++ program is available at ftp://ftp.ncbi.nih.gov/pub/spouge/papers/archive/AGLAM/2006-07-19

Algorithms↗

PubMed2000

Neuronal localization of sterol regulatory element binding protein-1 in the rodent and primate brain: a light and electron microscopic immunocytochemical study.

Sterol regulatory element binding proteins are membrane-bound transcription factors that activate expression of several genes controlling cellular cholesterol and fatty acid homeostasis. The present study aimed to investigate the in vivo expression of sterol regulatory element binding protein-1 in the normal rodent and primate brain, and in the brain in Niemann-Pick type C disease mice. These mutant animals have lysosomal cholesterol accumulation and progressive neurodegeneration caused by an inactivating mutation of the NPC1 gene whose protein product functions in vesicular lipid trafficking. Western blot analysis of rat hippocampal homogenates with an affinity purified rabbit polyclonal antibody directed against an internal epitope of sterol regulatory element binding protein-1 identified a major 68,000 mol. wt protein consistent with the amino-terminal, transcriptionally active fragment of sterol regulatory element binding proteins-1. Immunocytochemically, this antibody revealed dense sterol regulatory element binding protein-1 staining of nuclei and light staining of the cytoplasm of cells in the neocortex and hippocampus in the rat, mouse and monkey brain. By electron microscopy of immunogold-labeled brain sections, these densely labeled cells were found to be neurons. In contrast, normal glial cells had little or no sterol regulatory element binding protein-1 immunoreactivity even at a developmental stage (postnatal day 9) which coincides with active myelination in the rat brain. Also, in contrast to the normal mouse brain, Niemann-Pick type C mice showed reduced staining of cortical and hippocampal neuronal nuclei. Since sterol regulatory element binding protein-1 has been shown to be a transcriptional regulator of fatty acid synthesis in vivo, the current findings of a predominantly neuronal nuclear expression of the 68,000 mol. wt transcriptionally active fragment of sterol regulatory element binding protein-1 highlights the established role of phospholipid metabolites and other fatty-acid containing lipids in neuronal signal transduction and other neuronal functions. Reduced sterol regulatory element binding protein-1 expression in neurons in Niemann-Pick type C may reflect a deficiency in fatty acid synthesis that could contribute to the neuronal dysfunction in this disorder.

Animals↗

PubMed2006

Constitutive and IFNgamma-induced activation of MHC2TA promoter type III in human melanoma cell lines is governed by separate regulatory elements within the PIII upstream regulatory region.

Cell lines established from tumor tissue of cutaneous melanoma biopsies often display constitutive and IFNgamma-inducible expression of MHC class II molecules. The expression of MHC class II molecules in melanoma is associated with an overall poor prognosis and unfavorable clinical outcome. We have analyzed the DNA elements and interacting transcription factors that control the constitutive and IFNgamma-inducible expression of the class II transactivator (CIITA), a co-activator essential for transcription of all MHC class II genes. Our studies reveal the activation of multiple CIITA promoter regions (CIITA-PII, -PIII and -PIV) in melanoma cell lines for both the constitutive and IFNgamma-inducible expression of MHC class II molecules. Furthermore, we show that constitutive and IFNgamma-inducible expression of the CIITA-PIII isoform is governed by separate regulatory elements within the PIII upstream regulatory region (PURR). Similarly constitutive activation in melanoma of CIITA-PII, CIITA-PIII, and CIITA-PIV does not require components of the IFNgamma signaling pathway. However, these components are readily recruited to the PURR and CIITA-PIV after exposure of cells to IFNgamma and account for the IFNgamma-induced expression of CIITA. Together, our data reveal the contribution of distinct elements and factors in the constitutive and IFNgamma-inducible expression of CIITA in melanoma cell lines of the skin.

Antiviral Agents↗

PubMed1998

Human beta-myosin heavy chain mRNA prevalence is inversely related to the degree of methylation of regulatory elements.

OBJECTIVE: Methylation of cytosine in CG dinucleotides within regulatory elements is believed to silence gene expression. These dinucleotides occur in certain important regulatory elements in the promoter region of the human beta-myosin heavy chain (beta-MHC) gene. We therefore investigated whether methylation of these elements correlates with beta-MHC gene transcription in human 'expressing' (right atrial) and 'non-expressing' (peripheral blood leucocytes) cells. METHODS: We employed 2 techniques to assess promoter methylation: (i) analysis of the susceptibility to digestion of a particular CCGG restriction site in the promoter region when genomic DNA is cleaved with the restriction endonucleases MspI (methylation-insensitive) and HpaII (methylation-sensitive), and (ii) the bisulphite-PCR method to examine in detail the methylation patterns of 3 important regulatory elements that contain CG dinucleotides. beta-MHC mRNA expression in right atrium and leucocytes was assessed using reverse-transcription-PCR with specific primers that do not detect alpha-MHC cDNA. RESULTS: The digestion pattern observed with MspI or HpaII indicated that the CCGG site was almost completely methylated in leucocytes, but relatively unmethylated in atrial myocardium from the same patients. When methylation was examined with the bisulphite-PCR method we found a reciprocal relationship between the level of beta-MHC mRNA expression in leucocytes and atrial myocardium and the degree of methylation of CG dinucleotides in the 5' regulatory elements of the gene. CONCLUSIONS: Tissue-specific methylation of the human beta-MHC gene promoter may play a role in determining the pattern of expression of this gene. Furthermore, alteration of the level of methylation may underlie the changes in transcription of this gene that occur, for example, when atrial or ventricular myocardium hypertrophies.

Cardiomyopathy, Hypertrophic↗

PubMed2006

Identification of nerve growth factor-responsive element of the TCL1 promoter as a novel negative regulatory element.

The serine/threonine kinase, Akt (protein kinase B) plays a central role in the regulation of intracellular cell survival. Recently, we demonstrated that the proto-oncogene TCL1, overexpressed in human T-cell prolymphocytic leukemia, is an Akt kinase co-activator. Tightly restricted TCL1 gene expression in early developmental cells suggested that the TCL1 gene is regulated at a transcriptional level. To characterize how TCL1 gene expression is regulated, we cloned the 5'-promoter of the TCL1 gene located at human chromosome 14q32. The 5'-TCL1 promoter region contains a TATA box with cis-regulatory elements for Nur77/NGFI-B (nerve growth factor-responsive element (NBRE), CCAAGGTCA), NFkappaB, and fork head transcription factor. Nur77/NGFI-B, an orphan receptor superfamily transcription factor implicated in T-cell apoptosis, is a substrate for Akt. We hypothesized that TCL1 transactivity is regulated through Akt-induced phosphorylation of Nur77/NGFI-B in vivo. In an electrophoretic mobility shift assay with chromosomal immunoprecipitation assays, wild-type Nur77, but not S350A mutant Nur77, could specifically bind to TCL1-NBRE. A luciferase assay demonstrated that TCL1-NBRE is required for inhibition of TCL1 transactivity upon nerve growth factor/platelet-derived growth factor stimulation, which activates Akt and phosphorylates Nur77. Using a chromosomal immunoprecipitation assay with reverse transcription-PCR, nerve growth factor stimulation inhibited binding of endogenous Nur77 to TCL1-NBRE, in turn, suppressing TCL1 gene expression. The results together establish that TCL1-NBRE is a novel negative regulatory element of Nur77 (NGFI-B). To the best of our knowledge, TCL1-NBRE is the first direct target of Nur77 involving the regulation of intracellular cell death survival. This Akt-induced inhibitory mechanism of TCL1 should play an important role in immunological and/or neuronal development in vivo.

Animals↗

PubMed1997

Sterol regulation of acetyl coenzyme A carboxylase promoter requires two interdependent binding sites for sterol regulatory element binding proteins.

The sterol regulatory element binding proteins (SREBPs) are central regulators of lipid homeostasis in mammalian cells. Their activity is controlled by a sterol-regulated two-step proteolytic process that releases the nuclear targeted amino-terminal domain from the membrane anchored carboxyl-terminal remnant. This ensures that transcriptional stimulation of the appropriate genes occurs only when increased intracellular sterol accumulation is required. Gene targets for SREBP encode key proteins of cholesterol metabolism as well as essential proteins of fatty acid biosynthesis, providing a mechanism for coordinate control of these two major lipid pathways when sterols and fatty acids need to accumulate together. However, the regulatory mechanism must provide a way to uncouple these two pathways to allow separate regulation when sterol or fat levels need to increase independently of each other. We compared the similarities and differences for how SREBP activates the promoter for the low density lipoprotein (LDL) receptor, which is the key protein involved in cholesterol uptake, relative to how it activates promoters for acetyl coenzyme A carboxylase (ACC) and fatty acid synthase (FAS), which are both key enzymes of fatty acid biosynthesis. In the current studies we show there are two distinct sites for SREBP binding that control activation of the ACC PII promoter whereas previous work has shown there is only a single SREBP site in the LDL receptor. Additionally, disruption of either ACC site results in a total loss in promoter function and a severe decrease in SREBP binding even to the neighboring unaltered site. Thus, the two sites are equally important and dependent on one another for optimal function. This is in contrast to the FAS promoter where SREBP binds to two adjacent sites independently and the one located closer to the binding site for the Sp1 co-regulator is more critical for sterol regulation and activation by SREBP over-expression.

Acetyl-CoA Carboxylase↗

PubMed1998

Synergistic activation of transcription by nuclear factor Y and sterol regulatory element binding protein.

The current studies define the role of three distinct cis-elements in the proximal promoter of the rat farnesyl diphosphate (FPP) synthase gene. The three cis-elements, a sterol regulatory element 3 (SRE-3) flanked by an ATTGG motif (inverted CCAAT box), and a CCAAT box, form a sterol regulatory unit that is necessary and sufficient for sterol-regulated expression of FPP synthase promoter-reporter genes. FPP synthase promoter-reporter genes, that contain promoters with either wild-type nucleotide sequences or mutations in one or more of the three cis-elements, were transiently transfected into CV-1 cells. The activity of the wild-type promoter-reporter gene increased when the cells were incubated in sterol-depleted media or when the cells were co-transfected with a plasmid encoding the mature form of SRE binding protein (SREBP-1a). The results with the mutant promoter-reporter genes demonstrated that all three cis-elements were necessary for normal expression/regulation of the reporter gene by either sterols or by co-expressed SREBP-1a. Gel mobility shift assays demonstrated that the synergistic binding of SREBP-1a to SRE-3 was dependent on the binding of recombinant nuclear factor Y (NF-Y) to the DNA, consistent with the in vivo regulation studies.

Alkyl and Aryl Transferases↗

PubMed1999

The 5'-flanking sequence and regulatory elements of the cystatin S gene.

The gene encoding rat cystatin S (Cys S), a salivary gland-specific secretory protein, has CAAT and TATA boxes upstream of the inititation codon (Cox and Shaw, 1992), and contains regions that resemble those of other hormonally responsive eukaryotic genes. The 5'-flanking sequence of the rat Cys S gene has a potential CREB/AP-1 binding site (Rupp et al., 1990; Trejo et al., 1992), two potential glucocorticoid responsive elements (GREs, Drouin et al., 1989), and a possible GR/PR (glucocorticoid/progesterone) responsive element (Forman and Samuels, 1990). One of these potential GREs is adjacent to a potential AP-2 binding site, and another is typical of the glucocorticoid and progesterone receptor binding site. In this report, we have identified three regions in the 5'-flanking region of the Cys S gene that are found in salivary gland-specific genes (Ting et al., 1992) with a GT-rich region located between conserved elements II and III. Transfection experiments described in this paper suggest that a 281-bp DNA fragment from the Cys S gene promoter region with conserved elements II and III, the GT-rich region, and a possible GR/PR responsive element contains a negative regulatory element. In addition, our experiments suggest that the GT-rich region by itself is acting as a positive regulatory element.

Animals↗

PubMed1997

Structure of the human gene encoding sterol regulatory element binding protein 2 (SREBF2).

Sterol-regulatory element binding protein (SREBP) 1 and SREBP2 are ubiquitously expressed transcription factors that play key roles in the regulation of cholesterol and fatty acid metabolism. SREBP1 and SREBP2 share approximately 47% sequence identity and map to chromosomes 17 and 22, respectively. The gene encoding SREBP1 (SREBF1) has been cloned and characterized. In this paper we describe the gene structure and 5'-flanking sequence of SREBF2. SREBF2 spans 72 kb and is composed of 19 exons and 18 introns. The locations of the exon/intron boundaries of SREBF2 are remarkably similar to those of SREBF1, but SREBF2 is approximately 2.8 times larger in size. The 5'-flanking regions of SREBF2 and of two alternatively spliced forms of SREBF1, SREBF1a and SREBF1c, were sequenced, and the SREBF2 transcription start site was determined. A perfect 10-bp sterol regulatory element (SRE)-1 sequence was present in the promoter region of SREBF2. No SRE-1 was identified in the 5'-flanking sequences of either SREBF1a or SREBF1c, but several E-box sequences were present in SREBP1c. Thus, analysis of the 5'-flanking regions provides support that these two transcription factors, though similar in their coding sequence and overall gene structure, have different physiological roles. Finally, evidence is presented for the presence of another expressed gene of unknown function located 500 bp upstream of SREBF2.

Amino Acid Sequence↗

PubMed1998

Thyroid hormone direct repeat 4 response element is a positive regulatory element for the human TR2 orphan receptor, a member of steroid receptor superfamily.

We demonstrate that TR2 orphan receptor (TR2) may induce transactivation activities via an AGGTCA-like-direct-repeat-4 consensus thyroid hormone response element (DR4-TRE) system. TR2 showed a slightly greater binding affinity than thyroid hormone receptor alpha1 (TR alpha1)/retinoid X receptor alpha (RXR alpha) heterodimer with Kds 0.5 nM and 2.3 nM, respectively. These receptors, TR2 and TR alpha1/RXR alpha heterodimer, competed with each other on binding to limited amounts of DR4-TRE. TR2 canceled the suppression effect of unliganded-TR alpha1 on CAT reporter activity in a dose-dependent fashion. Estrogen receptor (ER) and 2P2 (a mutated TR2 with P box sequence of androgen receptor) failed not only to bind to DR4-TRE but also to recover this inhibitory effect of unliganded TRalpha1. However, when T3 was supplemented, estradiol-ER competed for a full CAT activity while TR2 showed an additive effect on the transcriptional activation. These results indicate that DNA binding is essential for TR2 to take action and fully functional liganded TR alpha1 may rely on common factors shared with ER but not TR2.

Carrier Proteins↗

PubMed1994

Purification and characterization of nuclear factors binding to the negative regulatory element D of human apolipoprotein A-II promoter: a negative regulatory effect is reversed by GABP, an Ets-related protein.

We have previously shown that transcription of the human apolipoprotein A-II (apoA-II) gene is controlled by a complex set of regulatory elements [Cardot et al. (1993) Biochemistry 32, 9080-9093]. We have also identified previously described, as well as new activities which bind to these elements and influence to varying degrees the transcription of the apoA-II gene. DNA binding and competition assays indicated that element D binds three new activities, designated AIID1, AIID2, and AIID4, as well as an activity related to C/EBP. Activities AIID1, AIID2, and AIID4 were purified and characterized further in order to determine their function on the transcriptional regulation of human apoA-II gene. SDS-PAGE analysis as well as photoaffinity cross-linking of the affinity-purified AIID2 showed that it consists of three proteins with molecular masses ranging between 54 and 63 kDa. The amino acid sequence of tryptic peptides obtained from AIID2 protein bands revealed that it is homologous to GABP, an Ets-related protein. Similar analysis showed that affinity-purified AIID4 has an apparent molecular mass of 130 kDa. AIID1 activity was purified partially; in addition to binding to the apoA-II promoter, AIID1 also binds to the regulatory element C of apoCIII and may play a role in the transcriptional regulation of both genes. Methylation interference of G residues and permanganate modification of T residues indicated that the binding sites of AIID2 and AIID4 were contiguous on element D. However, the binding site of AIID1 overlaps with the binding sites of both AIID2 and AIID4. This suggests that the binding of AIID1 and AIID2 or of AIID1 and AIID4 may be mutually exclusive, whereas AIID2 and AIID4 may bind simultaneously. Transcription from a minimal promoter containing elements AB, C, and D of apoA-II increased 1.5- to 1.6-fold when element D is deleted, as well as by promoter mutations which eliminated the binding of both AIID1 and/or AIID4 to element D, but permitted the binding of AIID2/GABP. The findings suggest that element D has a negative regulatory role on apoA-II gene transcription when it is occupied by protein AIID1 and/or AIID4. This negative effect is reversed when element D is occupied only by the regulatory factor AIID2/GABP.

Amino Acid Sequence↗

PubMed2003

Computational approaches to identify promoters and cis-regulatory elements in plant genomes.

The identification of promoters and their regulatory elements is one of the major challenges in bioinformatics and integrates comparative, structural, and functional genomics. Many different approaches have been developed to detect conserved motifs in a set of genes that are either coregulated or orthologous. However, although recent approaches seem promising, in general, unambiguous identification of regulatory elements is not straightforward. The delineation of promoters is even harder, due to its complex nature, and in silico promoter prediction is still in its infancy. Here, we review the different approaches that have been developed for identifying promoters and their regulatory elements. We discuss the detection of cis-acting regulatory elements using word-counting or probabilistic methods (so-called "search by signal" methods) and the delineation of promoters by considering both sequence content and structural features ("search by content" methods). As an example of search by content, we explored in greater detail the association of promoters with CpG islands. However, due to differences in sequence content, the parameters used to detect CpG islands in humans and other vertebrates cannot be used for plants. Therefore, a preliminary attempt was made to define parameters that could possibly define CpG and CpNpG islands in Arabidopsis, by exploring the compositional landscape around the transcriptional start site. To this end, a data set of more than 5,000 gene sequences was built, including the promoter region, the 5'-untranslated region, and the first introns and coding exons. Preliminary analysis shows that promoter location based on the detection of potential CpG/CpNpG islands in the Arabidopsis genome is not straightforward. Nevertheless, because the landscape of CpG/CpNpG islands differs considerably between promoters and introns on the one side and exons (whether coding or not) on the other, more sophisticated approaches can probably be developed for the successful detection of "putative" CpG and CpNpG islands in plants.

Computational Biology↗

PubMed2004

Identification of regulatory elements in the Plasmodium falciparum genome.

There is little information regarding regulatory sequences in the newly sequenced genome of the malaria parasite, Plasmodium falciparum. Thus, for the first time, a bioinformatic strategy was utilized to identify regulatory elements in this genome using the P. falciparum heat shock protein (hsp) gene family as a model system. Our analysis indicates that the P. falciparum hsp genes do not contain standard eukaryotic regulatory elements. However, a novel G-rich regulatory element named the G-box was identified upstream of several P. falciparum hsp genes and the P. yoelii yoelii, P. berghei, and P. vivax hsp86 genes. Remarkably, the Plasmodium sp. G-boxes were required for maximal reporter gene expression in transient transfection assays. The G-box is not homologous to known eukaryotic elements, and is the best-defined functional element elucidated from Plasmodium sp. Our analysis also revealed several other elements necessary for reporter gene expression including an upstream sequence element, the region surrounding the transcription start site, and the 5' and 3' untranslated regions. These data demonstrate that unique regulatory elements are conserved in the genomes of Plasmodium sp., and demonstrate the feasibility of bioinformatic approaches for their identification.

3' Untranslated Regions↗

PubMed2006

Computational identification of transcriptional regulatory elements in DNA sequence.

Identification and annotation of all the functional elements in the genome, including genes and the regulatory sequences, is a fundamental challenge in genomics and computational biology. Since regulatory elements are frequently short and variable, their identification and discovery using computational algorithms is difficult. However, significant advances have been made in the computational methods for modeling and detection of DNA regulatory elements. The availability of complete genome sequence from multiple organisms, as well as mRNA profiling and high-throughput experimental methods for mapping protein-binding sites in DNA, have contributed to the development of methods that utilize these auxiliary data to inform the detection of transcriptional regulatory elements. Progress is also being made in the identification of cis-regulatory modules and higher order structures of the regulatory sequences, which is essential to the understanding of transcription regulation in the metazoan genomes. This article reviews the computational approaches for modeling and identification of genomic regulatory elements, with an emphasis on the recent developments, and current challenges.

Animals↗