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We address the problem of comparing and characterizing the promoter regions of genes with similar expression patterns. This remains a challenging problem in sequence analysis, because often the promoter regions of co-expressed genes do not show discernible sequence conservation. In our approach, thus, we have not directly compared the nucleotide sequence of promoters. Instead, we have obtained predictions of transcription factor binding sites, annotated the predicted sites with the labels of the corresponding binding factors, and aligned the resulting sequences of labels--to which we refer here as transcription factor maps (TF-maps). To obtain the global pairwise alignment of two TF-maps, we have adapted an algorithm initially developed to align restriction enzyme maps. We have optimized the parameters of the algorithm in a small, but well-curated, collection of human-mouse orthologous gene pairs. Results in this dataset, as well as in an independent much larger dataset from the CISRED database, indicate that TF-map alignments are able to uncover conserved regulatory elements, which cannot be detected by the typical sequence alignments.
Signal transducer and activator of transcription 3 (STAT3) plays a critical role in leptin-mediated regulation of energy metabolism. This study investigated genetic variation in STAT3 promoter regions and verified their contribution to bovine body size traits. We first estimated the degree of conservation in STAT3, followed by measurements of its mRNA expression during fetal and adult stages of Qinchuan cattle. We then sequenced the STAT3 promoter region to determine genetic variants and evaluate their association with body size traits. From fetus to adult, STAT3 expression increased significantly in muscle, fat, heart, liver, and spleen tissues (p < 0.01), but decreased in the intestine, lung, and rumen (p < 0.01). We identified and named five single nucleotide polymorphisms (SNPs): SNP1-304A>C, SNP2-285G>A, SNP3-209A>C, SNP4-203A>G, and SNP5-188T>C. These five mutations fell significantly outside the Hardy-Weinberg equilibrium (HWE) (Chi-squared test, p < 0.05) and significantly associated with body size traits (p < 0.05). Individuals with haplotype H3H3 (CC-GG-CC-GG-CC) were larger in body size than other haplotypes. Therefore, variations in the STAT3 gene promoter regions, most notably haplotype H3H3, may benefit marker-assisted breeding of Qinchuan cattle.
Based on molecular information theory, 10 T7-like promoter models were built for the T7 group of phages and used to scan their host genomes and closely related genomes. 38 genomes were scanned and 12 clusters of tandem promoters were identified in nine enteropathogens. Comparative analysis of these tandem promoter-bearing regions reveals that they are similar to each other, forming prophage-like islands of 4-13 kb. Each island appears to contain two or three tandem T7-like promoters within a stretch of 150-620 bases, but there are no corresponding RNA polymerase (RNAP) genes. The promoters would transcribe two to five putative phage-related proteins, but none of these resemble known phage structural proteins. An integrase belonging to the Int family of site-specific recombinases is encoded upstream of the tandem promoters. A direct repeat of 17-24 bases was found on the ends of all 12 islands. Comparative analysis of the islands shows that these islands appear to have recombined with each other. These results suggest that the islands could encode a group of satellite phages. Activation and function of the islands may depend on transcription by a T7-like RNAP after infection by a T7-like phage or foreign DNA that encodes a T7-like RNAP.
The exploration of candidate immune response genes in goat may be vital in improving further our understanding about the species specific response to pathogens specifically among the ruminants. In this study, approximately 3.7 kb long genomic sequence of Toll-like receptor 5 (TLR5) covering the entire coding and 5'upstream regions of the gene, was characterized in the Indian goat breeds. Sequence analysis revealed a 2577-nucleotide long open reading frame (ORF) of goat TLR5, encoding 858 amino acids from single exon, similar to other ruminants. The domain structure analysis of goat TLR5 showed the presence of 13 leucine rich repeats (LRRs) in extracellular domain (amino acid position 1-634), single transmembrane domain (position 644-666), and a Toll/interleukin-1 receptor (position 692-837) in cytoplasmic domain, similar to other species. A total of 87 putative transcription factor binding sites were observed within the 5' upstream region of TLR5 gene in goat, 106 in cattle, and 103 in buffalo. Sixteen polymorphic sites were observed in goat TLR5 gene, out of which 10 non-synonymous SNPs were in the functionally important regions. However, none of the amino acid substitutions was found to be potentially damaging to the structure and function of the receptor protein. Further, one of the SNPs in the transmembrane region was genotyped by a TETRA-ARMS PCR in 444 goats of nine breeds from different geographical regions and having different utilities. A significant variation in allelic frequencies was observed across the milch and other types of goat breeds. The comparative modeling of goat TLR5 followed by molecular dynamics simulation gave an insight into its 3D structural arrangements. The molecular docking of Salmonella flagellin and TLR5 dimer elucidated LRRNT (N-terminal) to LRR4 as the key flagellin binding domains region in goat TLR5. The study shows that, although being highly conserved among the ruminants, comparatively high variations in goat TLR5 might give an opportunity to host for recognizing the wider spectrum of pathogens.
Proximal promoter regions (PPR) are heavily transcribed yielding different types of small RNAs. The act of transcription within PPRs might regulate downstream gene expression via transcriptional interference (TI). For analysis, we investigated capped and polyadenylated small RNA transcripts within PPRs of human RefSeq genes in eight different cell lines. Transcripts of our datasets overlapped with experimentally determined transcription factor binding sites (TFBS). For TFBSs intersected by these small RNA transcripts, we established negative correlation of sRNA expression levels and transcription factor (TF) DNA binding affinities; suggesting that the transcripts acted via TI. Accordingly, datasets were designated as TFbiTrs (TF-binding interfering transcripts). Expression of most TFbiTrs was restricted to certain cell lines. This facilitated the analysis of effects related to TFbiTr expression for the same RefSeq genes across cell lines. We consistently uncovered higher relative TF/DNA binding affinities and concomitantly higher expression levels for RefSeq genes in the absence of TFbiTrs. Analysis of corresponding chromatin landscapes supported these results. ChIA-PET revealed the participation of distal enhancers in TFbiTr transcription. Enhancers regulating TFbiTrs, in effect, act as repressors for corresponding downstream RefSeq genes. We demonstrate the significant impact of TI on gene expression using selected small RNA datasets.
Pathogenic variations in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene are responsible for multiple epilepsy phenotypes, including Dravet syndrome, febrile seizures (FS) and genetic epilepsy with FS plus. Phenotypic heterogeneity is a hallmark of SCN1A-related epilepsies, the causes of which are yet to be clarified. Genetic variation in the non-coding regulatory regions of SCN1A could be one potential causal factor. However, a comprehensive understanding of the SCN1A regulatory landscape is currently lacking. Here, we summarized the current state of knowledge of SCN1A regulation, providing details on its promoter and enhancer regions. We then integrated currently available data on SCN1A promoters by extracting information related to the SCN1A locus from genome-wide repositories and clearly defined the promoter and enhancer regions of SCN1A. Further, we explored the cellular specificity of differential SCN1A promoter usage. We also reviewed and integrated the available human brain-derived enhancer databases and mouse-derived data to provide a comprehensive computationally developed summary of SCN1A brain-active enhancers. By querying genome-wide data repositories, extracting SCN1A-specific data and integrating the different types of independent evidence, we created a comprehensive catalogue that better defines the regulatory landscape of SCN1A, which could be used to explore the role of SCN1A regulatory regions in disease.
Previous observations have demonstrated that embryonic exposure to the endocrine disruptor vinclozolin during gonadal sex determination promotes transgenerational adult onset disease such as male infertility, kidney disease, prostate disease, immune abnormalities and tumor development. The current study investigates genome-wide promoter DNA methylation alterations in the sperm of F3 generation rats whose F0 generation mother was exposed to vinclozolin. A methylated DNA immunoprecipitation with methyl-cytosine antibody followed by a promoter tilling microarray (MeDIP-Chip) procedure was used to identify 52 different regions with statistically significant altered methylation in the sperm promoter epigenome. Mass spectrometry bisulfite analysis was used to map the CpG DNA methylation and 16 differential DNA methylation regions were confirmed, while the remainder could not be analyzed due to bisulfite technical limitations. Analysis of these validated regions identified a consensus DNA sequence (motif) that associated with 75% of the promoters. Interestingly, only 16.8% of a random set of 125 promoters contained this motif. One candidate promoter (Fam111a) was found to be due to a copy number variation (CNV) and not a methylation change, suggesting initial alterations in the germline epigenome may promote genetic abnormalities such as induced CNV in later generations. This study identifies differential DNA methylation sites in promoter regions three generations after the initial exposure and identifies common genome features present in these regions. In addition to primary epimutations, a potential indirect genetic abnormality was identified, and both are postulated to be involved in the epigenetic transgenerational inheritance observed. This study confirms that an environmental agent has the ability to induce epigenetic transgenerational changes in the sperm epigenome.
Developmental gene expression results from the orchestrated interplay between genetic and epigenetic mechanisms. Here, we describe upSET, a transcriptional regulator encoding a SET domain-containing protein recruited to active and inducible genes in Drosophila. However, unlike other Drosophila SET proteins associated with gene transcription, UpSET is part of an Rpd3/Sin3-containing complex that restricts chromatin accessibility and histone acetylation to promoter regions. In the absence of UpSET, active chromatin marks and chromatin accessibility increase and spread to genic and flanking regions due to destabilization of the histone deacetylase complex. Consistent with this, transcriptional noise increases, as manifest by activation of repetitive elements and off-target genes. Interestingly, upSET mutant flies are female sterile due to upregulation of key components of Notch signaling during oogenesis. Thus UpSET defines a class of metazoan transcriptional regulators required to fine tune transcription by preventing the spread of active chromatin.
The bromodomain containing 1 gene, BRD1 is essential for embryogenesis and CNS development. It encodes a protein that participates in histone modifying complexes and thereby regulates the expression of a large number of genes. Genetic variants in the BRD1 locus show association with schizophrenia and bipolar disorder and risk alleles in the promoter region correlate with reduced BRD1 expression. Insights into the transcriptional regulation of BRD1 and the pathogenic mechanisms associated with BRD1 risk variants, however, remain sparse. By studying transcripts in human HeLa and SH-SY5Y cells we provide evidence for differences in relative expression of BRD1 transcripts with three alternative 5' UTRs (exon 1C, 1B, and 1A). We further show that expression of these transcript variants covaries negatively with DNA methylation proportions in their upstream promoter regions suggesting that promoter usage might be regulated by DNA methylation. In line with findings that the risk allele of the rs138880 SNP in the BRD1 promoter region correlates with reduced BRD1 expression, we find that it is also associated with moderate regional BRD1 promoter hypermethylation in both adipose tissue and blood. Importantly, we demonstrate by inspecting available DNA methylation and expression data that these regions undergo changes in methylation during fetal brain development and that differences in their methylation proportions in fetal compared to postnatal frontal cortex correlate significantly with BRD1 expression. These findings suggest that BRD1 may be dysregulated in both the developing and mature brain of risk allele carriers. Finally, we demonstrate that commonly used mood stabilizers Lithium, Valproate, and Carbamazepine affect the expression of BRD1 in SH-SY5Y cells. Altogether this study indicates a link between genetic risk and epigenetic dysregulation of BRD1 which raises interesting perspectives for targeting the mechanisms pharmacologically.
Sox17 gene expression is essential for both endothelial and endodermal cell differentiation. To better understand the genetic basis for the expression of multiple Sox17 mRNA forms, we identified and performed CRISPR/Cas9 mutagenesis of two evolutionarily conserved promoter regions (CRs). The deletion of the upstream and endothelial cell-specific CR1 caused only a modest increase in lympho-vasculogenesis likely via reduced Notch signaling downstream of SOX17. In contrast, the deletion of the downstream CR2 region, which functions in both endothelial and endodermal cells, impairs both vascular and endodermal development causing death by embryonic day 12.5. Analyses of 3D chromatin looping, transcription factor binding, histone modification, and chromatin accessibility data at the Sox17 locus and surrounding region further support differential regulation of the two promoters during the development.
The molecular mechanism of olfactory cognition is very complicated. Olfactory cognition is initiated by olfactory receptor proteins (odorant receptors), which are activated by olfactory stimuli (ligands). Olfactory receptors are the initial player in the signal transduction cascade producing a nerve impulse, which is transmitted to the brain. The sensitivity to a particular ligand depends on the expression level of multiple proteins involved in the process of olfactory cognition: olfactory receptor proteins, proteins that participate in signal transduction cascade, etc. The expression level of each gene is controlled by its regulatory regions, and especially, by the promoter [a region of DNA about 100-1000 base pairs long located upstream of the transcription start site (TSS)]. We analyzed single nucleotide polymorphisms using human whole-genome data from the 1000 Genomes Project and revealed an extremely high level of single nucleotide polymorphisms in promoter regions of olfactory receptor genes and HLA genes. We hypothesized that the high level of polymorphisms in olfactory receptor promoters was responsible for the diversity in regulatory mechanisms controlling the expression levels of olfactory receptor proteins. Such diversity of regulatory mechanisms may cause the great variability of olfactory cognition of numerous environmental olfactory stimuli perceived by human beings (air pollutants, human body odors, odors in culinary etc.). In turn, this variability may provide a wide range of emotional and behavioral reactions related to the vast variety of olfactory stimuli.
Gene expression is to large degree regulated by the specific binding of protein transcription factors to cis-regulatory transcription factor binding sites in gene promoter regions. Despite the identification of hundreds of binding site sequence motifs, the question as to whether motif orientation matters with regard to the gene expression regulation of the respective downstream genes appears surprisingly underinvestigated.
Altered DNA methylation in addiction-related genes may modify the susceptibility to alcohol or drug dependence (AD or ND). We profiled peripheral blood DNA methylation levels of 384 CpGs in promoter regions of 82 addiction-related genes in 256 African Americans (AAs) (117 cases with AD-ND codependence and 139 controls) and 196 European Americans (103 cases with AD-ND codependence and 93 controls) using Illumina's GoldenGate DNA methylation array assays. AD-ND codependence-associated DNA methylation changes were analyzed using linear mixed-effects models with consideration of batch effects and covariates age, sex, and ancestry proportions. Seventy CpGs (in 41 genes) showed nominally significant associations (P < 0.05) with AD-ND codependence in both AAs and EAs. One CpG (HTR2B cg27531267) was hypomethylated in AA cases (P = 7.2 × 10-5), while 17 CpGs in 16 genes (including HTR2B cg27531267) were hypermethylated in EA cases (5.6 × 10-9 ≤ P ≤ 9.5 × 10-5). Nevertheless, 13 single nucleotide polymorphisms (SNPs) nearby HTR2B cg27531267 and the interaction of these SNPs and cg27531267 did not show significant effects on AD-ND codependence in either AAs or EAs. Our study demonstrated that DNA methylation changes in addiction-related genes could be potential biomarkers for AD-ND co-dependence. Future studies need to explore whether DNA methylation alterations influence the risk of AD-ND codependence or the other way around.
The recent release of the domestic dog genome provides us with an ideal opportunity to investigate dog-specific genomic features. In this study, we performed a systematic analysis of CpG islands (CGIs), which are often considered gene markers, in the dog genome. Relative to the human and mouse genomes, the dog genome has a remarkably large number of CGIs and high CGI density, which is contributed by its noncoding sequences. Surprisingly, the dog genome has fewer CGIs associated with the promoter regions of genes than the human or the mouse. Further examination of functional features of dog-human-mouse homologous genes suggests that the dog might have undergone a faster erosion rate of promoter-associated CGIs than the human or mouse. Some genetic or genomic factors such as local recombination rate and karyotype may be related to the unique dog CGI features.
Identifying the key factors that underlie complex traits during domestication is a great challenge for evolutionary and biological studies. In addition to the protein-coding region differences caused by variants, a large number of variants are located in the noncoding regions containing multiple types of regulatory elements. However, the roles of accumulated variants in gene regulatory elements during duck domestication and economic trait improvement are poorly understood.
Bidirectional promoters are defined as those that regulate adjacent genes organized in a divergent fashion (head to head orientation) and separated by <1 kb. In order to dissect bidirectional promoter activity in a model plant, deletion analysis was performed for seven rice promoters using promoter-reporter gene constructs, which identified three promoters to be bidirectional. Regulatory elements located in or close to the 5'-untranslated regions (UTR) of one of the genes (divergent gene pair) were found to be responsible for their bidirectional activity. DNA footprinting analysis identified unique protein binding sites in these promoters. Deletion/alteration of these motifs resulted in significant loss of expression of the reporter genes on either side of the promoter. Changes in the motifs at both the positions resulted in a remarkable decrease in bidirectional activity of the reporter genes flanking the promoter. Based on our results, we propose a novel mechanism for the bidirectionality of rice bidirectional promoters.
The regulation of the brain-derived neurotrophic factor (BDNF) is important for depression pathophysiology and epigenetic regulation of the BDNF gene may be involved. This study investigated whether BDNF methylation is a marker of depression. One thousand and twenty-four participants were recruited as part of a longitudinal study of psychiatric disorders in general population elderly (age ⩾ 65). Clinical levels of depression were assessed using the Mini International Neuropsychiatric Interview for the diagnosis of major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorder IV criteria, and the Centre for Epidemiologic Studies Depression Scale (CES-D) for assessment of moderate to severe depressive symptoms. Buccal DNA methylation at the two most widely studied BDNF promoters, I and IV, was investigated using the Sequenom MassARRAY platform that allows high-throughput investigation of methylation at individual CpG sites within defined genomic regions. In multivariate linear regression analyses adjusted for a range of participant characteristics including antidepressant use, depression at baseline, as well as chronic late-life depression over the 12-year follow-up, were associated with overall higher BDNF methylation levels, with two sites showing significant associations (promoter I, Δ mean = 0.4%, P = 0.0002; promoter IV, Δ mean = 5.4%, P = 0.021). Three single-nucleotide polymorphisms (rs6265, rs7103411 and rs908867) were also found to modify the association between depression and promoter I methylation. As one of the largest epigenetic studies of depression, and the first investigating BDNF methylation in buccal tissue, our findings highlight the potential for buccal BDNF methylation to be a biomarker of depression.
An accurate identification of gene promoters remains an important challenge. Computational approaches for this problem rely on promoter sequence attributes that are believed to be critical for transcription initiation. Here we report a probabilistic model that captures two important properties of promoters, not used by previous methods, viz., the location preference and co-occurrence of promoter elements. Additionally, we found that many of the position-specific DNA elements are strongly linked with the function of the gene product. For instance, a highly conserved motif CCTTT at -1 position is strongly associated with protein synthesis, cellular and tissue development. Our comparative analysis of promoter classes reveals that the promoters devoid of CpG islands are more conserved and have fewer alternative transcription start sites. The discovered links between promoter elements and gene function allows us to infer genetic networks from promoter elements. The web server for the PSPA promoter predictor is available at /PSPA.
Mutations in basal core promoter (BCP) and precore regions of hepatitis B virus (HBV) are associated with course and treatment outcomes of chronic HBV infection. While BCP and precore mutation analysis have been carried out in adult patients between different genotypes, this analysis has rarely been performed for chronically infected children.
The matrix metalloproteinases (MMPs) are enzymes that cleave various components of the extracellular matrix (ECM) and basement membranes. MMPs are expressed in melanocytes and their overexpression has been linked to tumor development, progression and metastasis. At the genetic level, the following functional promoter polymorphisms are known to modify the gene transcription: -1306 C/T and -735 C/T in the MMP2 gene, and -1171 5A/6A in the MMP3 gene. Functional polymorphisms in MMP genes' promoter regions may modulate the risk for melanoma progression.
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