TBP facilitates RNA Polymerase I transcription following mitosis.

The TATA-box binding protein (TBP) is the sole transcription factor common in the initiation complexes of the three major eukaryotic RNA Polymerases (Pol I, II and III). Although TBP is central to transcription by the three RNA Pols in various species, the emergence of TBP paralogs throughout evolution has expanded the complexity in transcription initiation. Furthermore, recent studies have emerged that questioned the centrality of TBP in mammalian cells, particularly in Pol II transcription, but the role of TBP and its paralogs in Pol I transcription remains to be re-evaluated. In this report, we show that in murine embryonic stem cells TBP localizes onto Pol I promoters, whereas the TBP paralog TRF2 only weakly associates to the Spacer Promoter of rDNA, suggesting that it may not be able to replace TBP for Pol I transcription. Importantly, acute TBP depletion does not fully disrupt Pol I occupancy or activity on ribosomal RNA genes, but TBP binding in mitosis leads to efficient Pol I reactivation following cell division. These findings provide a more nuanced role for TBP in Pol I transcription in murine embryonic stem cells.

Papillary Thyroid Cancer Remodels the Genetic Information Processing Pathways.

The genetic causes of the differentiated, highly treatable, and mostly non-fatal papillary thyroid cancer (PTC) are not yet fully understood. The mostly accepted PTC etiology blames the altered sequence or/and expression level of certain biomarker genes. However, tumor heterogeneity and the patient's unique set of favoring factors question the fit-for-all gene biomarkers. Publicly accessible gene expression profiles of the cancer nodule and the surrounding normal tissue from a surgically removed PTC tumor were re-analyzed to determine the cancer-induced alterations of the genomic fabrics responsible for major functional pathways. Tumor data were compared with those of standard papillary and anaplastic thyroid cancer cell lines. We found that PTC regulated numerous genes associated with DNA replication, repair, and transcription. Results further indicated that changes of the gene networking in functional pathways and the homeostatic control of transcript abundances also had major contributions to the PTC phenotype occurrence. The purpose to proliferate and invade the entire gland may explain the substantial transcriptomic differences we detected between the cells of the cancer nodule and those spread in homo-cellular cultures (where they need only to survive). In conclusion, the PTC etiology should include the complex molecular mechanisms involved in the remodeling of the genetic information processing pathways.

Taf1 knockout is lethal in embryonic male mice and heterozygous females show weight and movement disorders.

The TATA box-binding protein-associated factor 1 (TAF1) is a ubiquitously expressed protein and the largest subunit of the basal transcription factor TFIID, which plays a key role in initiation of RNA polymerase II-dependent transcription. TAF1 missense variants in human males cause X-linked intellectual disability, a neurodevelopmental disorder, and TAF1 is dysregulated in X-linked dystonia-parkinsonism, a neurodegenerative disorder. However, this field has lacked a genetic mouse model of TAF1 disease to explore its mechanism in mammals and treatments. Here, we generated and validated a conditional cre-lox allele and the first ubiquitous Taf1 knockout mouse. We discovered that Taf1 deletion in male mice was embryonically lethal, which may explain why no null variants have been identified in humans. In the brains of Taf1 heterozygous female mice, no differences were found in gross structure, overall expression and protein localisation, suggesting extreme skewed X inactivation towards the non-mutant chromosome. Nevertheless, these female mice exhibited a significant increase in weight, weight with age, and reduced movement, suggesting that a small subset of neurons was negatively impacted by Taf1 loss. Finally, this new mouse model may be a future platform for the development of TAF1 disease therapeutics.

Dissection of core promoter syntax through single nucleotide resolution modeling of transcription initiation.

Our understanding of how the DNA sequences of cis-regulatory elements encode transcription initiation patterns remains limited. Here we introduce CLIPNET, a deep learning model trained on population-scale PRO-cap data that accurately predicts the position and quantity of transcription initiation with single nucleotide resolution from DNA sequence. Interpretation of CLIPNET revealed a complex regulatory syntax consisting of DNA-protein interactions in five major positions between -200 and +50 bp relative to the transcription start site, as well as more subtle positional preferences among different transcriptional activators. Transcriptional activator and core promoter motifs occupy different positions and play distinct roles in regulating initiation, with the former driving initiation quantity and the latter initiation position. We identified core promoter motifs that explain initiation patterns in the majority of promoters and enhancers, including DPR motifs and AT-rich TBP binding sequences in TATA-less promoters. Our results provide insights into the sequence architecture governing transcription initiation.

TAF1 is needed for the proliferation and maturation of thyroid follicle cells via Notch signaling.

Thyroid dysgenesis (TD) is the common pathogenic mechanism of congenital hypothyroidism (CH). In addition, known pathogenic genes are limited to those that are directly involved in thyroid development. To identify additional candidate pathogenetic genes, we performed forward genetic screening for TD in zebrafish, followed by positional cloning. The candidate gene was confirmed in vitro using the Nthy-ori 3.1 cell line and in vivo using a zebrafish model organism. We obtained a novel zebrafish line with thyroid dysgenesis and identified the candidate pathogenetic mutation TATA-box binding protein associated Factor 1 (taf1) by positional cloning. Further molecular studies revealed that taf1 was needed for the proliferation of thyroid follicular cells by binding to the NOTCH1 promoter region. Knockdown of TAF1 impaired the proliferation and maturation of thyroid cells, thereby leading to thyroid dysplasia. This study showed that TAF1 promoted Notch signaling and that this association played a pivotal role in thyroid development.NEW & NOTEWORTHY In our study, we obtained a novel zebrafish line with thyroid dysgenesis (TD) and identified the candidate pathogenetic mutation TATA-box binding protein associated Factor 1 (taf1). Further researches revealed that taf1 was required for thyroid follicular cells by binding to the NOTCH1 promoter region. Our findings revealed a novel role of TAF1 in thyroid morphogenesis.

AtSNP_TATAdb: Candidate Molecular Markers of Plant Advantages Related to Single Nucleotide Polymorphisms within Proximal Promoters of Arabidopsis thaliana L.

The mainstream of the post-genome target-assisted breeding in crop plant species includes biofortification such as high-throughput phenotyping along with genome-based selection. Therefore, in this work, we used the Web-service Plant_SNP_TATA_Z-tester, which we have previously developed, to run a uniform in silico analysis of the transcriptional alterations of 54,013 protein-coding transcripts from 32,833 Arabidopsis thaliana L. genes caused by 871,707 SNPs located in the proximal promoter region. The analysis identified 54,993 SNPs as significantly decreasing or increasing gene expression through changes in TATA-binding protein affinity to the promoters. The existence of these SNPs in highly conserved proximal promoters may be explained as intraspecific diversity kept by the stabilizing natural selection. To support this, we hand-annotated papers on some of the Arabidopsis genes possessing these SNPs or on their orthologs in other plant species and demonstrated the effects of changes in these gene expressions on plant vital traits. We integrated in silico estimates of the TBP-promoter affinity in the AtSNP_TATAdb knowledge base and showed their significant correlations with independent in vivo experimental data. These correlations appeared to be robust to variations in statistical criteria, genomic environment of TATA box regions, plants species and growing conditions.

NDRG1 promotes endothelial dysfunction and hypoxia-induced pulmonary hypertension by targeting TAF15.

Background: Pulmonary hypertension (PH) represents a threatening pathophysiologic state that can be induced by chronic hypoxia and is characterized by extensive vascular remodeling. However, the mechanism underlying hypoxia-induced vascular remodeling is not fully elucidated. Methods and Results: By using quantitative polymerase chain reactions, western blotting, and immunohistochemistry, we demonstrate that the expression of N-myc downstream regulated gene-1 (NDRG1) is markedly increased in hypoxia-stimulated endothelial cells in a time-dependent manner as well as in human and rat endothelium lesions. To determine the role of NDRG1 in endothelial dysfunction, we performed loss-of-function studies using NDRG1 short hairpin RNAs and NDRG1 over-expression plasmids. In vitro, silencing NDRG1 attenuated proliferation, migration, and tube formation of human pulmonary artery endothelial cells (HPAECs) under hypoxia, while NDRG1 over-expression promoted these behaviors of HPAECs. Mechanistically, NDRG1 can directly interact with TATA-box binding protein associated factor 15 (TAF15) and promote its nuclear localization. Knockdown of TAF15 abrogated the effect of NDRG1 on the proliferation, migration and tube formation capacity of HPAECs. Bioinformatics studies found that TAF15 was involved in regulating PI3K-Akt, p53, and hypoxia-inducible factor 1 (HIF-1) signaling pathways, which have been proved to be PH-related pathways. In addition, vascular remodeling and right ventricular hypertrophy induced by hypoxia were markedly alleviated in NDRG1 knock-down rats compared with their wild-type littermates. Conclusions: Taken together, our results indicate that hypoxia-induced upregulation of NDRG1 contributes to endothelial dysfunction through targeting TAF15, which ultimately contributes to the development of hypoxia-induced PH.

A comparative analysis of stably expressed genes across diverse angiosperms exposes flexibility in underlying promoter architecture.

Promoters regulate both the amplitude and pattern of gene expression-key factors needed for optimization of many synthetic biology applications. Previous work in Arabidopsis found that promoters that contain a TATA-box element tend to be expressed only under specific conditions or in particular tissues, while promoters that lack any known promoter elements, thus designated as Coreless, tend to be expressed more uniformly. To test whether this trend represents a conserved promoter design rule, we identified stably expressed genes across multiple angiosperm species using publicly available RNA-seq data. Comparisons between core promoter architectures and gene expression stability revealed differences in core promoter usage in monocots and eudicots. Furthermore, when tracing the evolution of a given promoter across species, we found that core promoter type was not a strong predictor of expression pattern. Our analysis suggests that core promoter types are correlative rather than causative in promoter expression patterns and highlights the challenges in finding or building constitutive promoters that will work across diverse plant species.

Dicarboxylic Amino Acid Permease 7219 Regulates Fruiting Body Type of Auricularia heimuer.

Auricularia heimuer is a widely cultivated jelly mushroom. The fruiting bodies are categorized into cluster and chrysanthemum types. With changing consumer demands and the need to reduce bio-waste, the demand for clustered fruiting bodies is increasing. Therefore, gene mining for fruiting body types is a matter of urgency. We determined that the A. heimuer locus for fruiting body type was located at one end of the genetic linkage map. The locus was localized between the markers D23860 and D389 by increasing the density of the genetic linkage map. BlastN alignment showed that the marker SCL-18 was also located between D23860 and D389, and a total of 25 coding genes were annotated within this interval. Through parental transcriptome analysis and qRT-PCR verification, the locus g7219 was identified as the gene controlling the fruiting body type. A single-nucleotide substitution in the TATA box of g7219 was detected between the parents. By PCR amplification of the promoter region of g7219, the TATA-box sequences of the cluster- and chrysanthemum-type strains were found to be CATAAAA and TATAAAA, respectively. This study provides a foundation for the breeding of fruiting body types and strain improvement of A. heimuer.

TAF1D Functions as a Novel Biomarker in Osteosarcoma.

Background: The most frequent primary bone cancer in teenagers, osteosarcoma (OS), is particularly aggressive with a high mortality rate. Methods: By combining public databases, OS and non-cancer samples were obtained. The Wilcoxon test and standardized mean difference (SMD) were utilized to evaluate the mRNA expression level of TATA-box binding protein associated factor, RNA polymerase 1 subunit D (TAF1D). The potential of TAF1D to discriminate OS samples from non-cancer samples was revealed by summary receiver operating characteristic curve (sROC). To investigate the prognostic significance, Kaplan‒Meier curve and univariate Cox analysis were performed. Immunohistochemistry (IHC) was used to determine the TAF1D protein expression level. ESTIMATE algorithm and TIMER2.0 database were used to reveal the association between TAF1D expression and the immune microenvironment. Enrichment analysis and potential drug prediction were performed to clarify the underlying molecular mechanisms and possible therapeutic directions of TAF1D. Ultimately, the transcription factors (TFs) and the TAF1D binding site were predicted based on the Cistrome and JASPAR databases. Results: TAF1D was upregulated in OS at the mRNA and protein levels and possessed robust discriminatory power. TAF1D upregulation was suggestive of worse prognosis and enhancement of tumor purity in OS patients. The cell cycle was the most significantly enriched pathway, and NU.1025 was considered to be the potential target agent. Finally, MYC was identified as a TF that regulates the expression of TAF1D. Conclusions: Altogether, TAF1D has the potential to serve as a biological marker and therapeutic target in OS, which could offer new perspectives for OS treatment.

TATA-box-binding protein-associated factor 15 is a novel biomarker that promotes cell proliferation and migration in gastrointestinal stromal tumor.

BACKGROUND: Gastrointestinal stromal tumor (GIST) is a common neoplasm with high rates of recurrence and metastasis, and its therapeutic efficacy is still not ideal. There is an unmet need to find new molecular therapeutic targets for GIST. TATA-box-binding protein-associated factor 15 (TAF15) contributes to the progress of various tumors, while the role and molecular mechanism of TAF15 in GIST progression are still unknown. AIM: To explore new molecular therapeutic targets for GIST and understand the biological role and underlying mechanisms of TAF15 in GIST progression. METHODS: Proteomic analysis was performed to explore the differentially expressed proteins in GIST. Western blotting and immunohistochemical analysis were used to verify the expression level of TAF15 in GIST tissues and cell lines. Cell counting kit-8, colony formation, wound-healing and transwell assay were executed to detect the ability of TAF15 on cell proliferation, migration and invasion. A xenograft mouse model was applied to explore the role of TAF15 in the progression of GIST. Western blotting was used to detect the phosphorylation level and total level of RAF1, MEK and ERK1/2. RESULTS: A total of 1669 proteins were identified as differentially expressed proteins with 762 upregulated and 907 downregulated in GIST. TAF15 was selected for the further study because of its important role in cell proliferation and migration. TAF15 was significantly over expressed in GIST tissues and cell lines. Overexpression of TAF15 was associated with larger tumor size and higher risk stage of GIST. TAF15 knockdown significantly inhibited the cell proliferation and migration of GIST in vitro and suppressed tumor growth in vivo. Moreover, the inhibition of TAF15 expression significantly decreased the phosphorylation level of RAF1, MEK and ERK1/2 in GIST cells and xenograft tissues, while the total RAF1, MEK and ERK1/2 had no significant change. CONCLUSION: TAF15 is over expressed in GIST tissues and cell lines. Overexpression of TAF15 was associated with a poor prognosis of GIST patients. TAF15 promotes cell proliferation and migration in GIST via the activation of the RAF1/MEK/ERK signaling pathway. Thus, TAF15 is expected to be a novel latent molecular biomarker or therapeutic target of GIST.

Promoter generation for the chimeric sex-determining gene dm-W in Xenopus frogs.

Many sex-determining genes (SDGs) were generated as neofunctionalized genes through duplication and/or mutation of gonadal formation-related genes. We previously identified dm-W as an SDG in the African clawed frog Xenopus laevis and found that a partial duplication of the masculinization gene dmrt1 created the neofunctionalized dm-W after allotetraploidization by interspecific hybridization. The allotetraploid Xenopus species have two dmrt1 genes, dmrt1.L and dmrt1.S. Xenopus laevis dm-W has four exons: two dmrt1.S-derived exons (exons 2 and 3) and two other exons (noncoding exon 1 and exon 4). Our recent work revealed that exon 4 originated from a DNA transposon, hAT-10. Here, to clarify when and how the noncoding exon 1 and its coexisting promoter evolved during the establishment of dm-W after allotetraploidization, we newly determined nucleotide sequences of the dm-W promoter region from two other allotetraploid species, X. largeni and X. petersii, and performed an evolutionary analysis. We found that dm-W acquired a new exon 1 and TATA-type promoter in the common ancestor of the three allotetraploid Xenopus species, resulting in the deletion of the dmrt1.S-derived TATA-less promoter. In addition, we demonstrated that the TATA box contributes to dm-W promoter activity in cultured cells. Collectively, these findings suggest that this novel TATA-type promoter was important for the establishment of dm-W as a sex-determining gene, followed by the degeneration of the preexisting promoter.

Investigating the sequence landscape in the Drosophila initiator core promoter element using an enhanced MARZ algorithm.

The core promoter elements are important DNA sequences for the regulation of RNA polymerase II transcription in eukaryotic cells. Despite the broad evolutionary conservation of these elements, there is extensive variation in the nucleotide composition of the actual sequences. In this study, we aim to improve our understanding of the complexity of this sequence variation in the TATA box and initiator core promoter elements in Drosophila melanogaster. Using computational approaches, including an enhanced version of our previously developed MARZ algorithm that utilizes gapped nucleotide matrices, several sequence landscape features are uncovered, including an interdependency between the nucleotides in position 2 and 5 in the initiator. Incorporating this information in an expanded MARZ algorithm improves predictive performance for the identification of the initiator element. Overall our results demonstrate the need to carefully consider detailed sequence composition features in core promoter elements in order to make more robust and accurate bioinformatic predictions.

Candidate SNP Markers Significantly Altering the Affinity of TATA-Binding Protein for the Promoters of Human Hub Genes for Atherogenesis, Atherosclerosis and Atheroprotection.

Atherosclerosis is a systemic disease in which focal lesions in arteries promote the build-up of lipoproteins and cholesterol they are transporting. The development of atheroma (atherogenesis) narrows blood vessels, reduces the blood supply and leads to cardiovascular diseases. According to the World Health Organization (WHO), cardiovascular diseases are the leading cause of death, which has been especially boosted since the COVID-19 pandemic. There is a variety of contributors to atherosclerosis, including lifestyle factors and genetic predisposition. Antioxidant diets and recreational exercises act as atheroprotectors and can retard atherogenesis. The search for molecular markers of atherogenesis and atheroprotection for predictive, preventive and personalized medicine appears to be the most promising direction for the study of atherosclerosis. In this work, we have analyzed 1068 human genes associated with atherogenesis, atherosclerosis and atheroprotection. The hub genes regulating these processes have been found to be the most ancient. In silico analysis of all 5112 SNPs in their promoters has revealed 330 candidate SNP markers, which statistically significantly change the affinity of the TATA-binding protein (TBP) for these promoters. These molecular markers have made us confident that natural selection acts against underexpression of the hub genes for atherogenesis, atherosclerosis and atheroprotection. At the same time, upregulation of the one for atheroprotection promotes human health.

Core Promoter Regions of Antisense and Long Intergenic Non-Coding RNAs.

RNA polymerase II (POL II) is responsible for the transcription of messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs). Previously, we have shown the evolutionary invariance of the structural features of DNA in the POL II core promoters of the precursors of mRNAs. In this work, we have analyzed the POL II core promoters of the precursors of lncRNAs in Homo sapiens and Mus musculus genomes. Structural analysis of nucleotide sequences in positions -50, +30 bp in relation to the TSS have shown the extremely heterogeneous 3D structure that includes two singular regions - hexanucleotide "INR" around the TSS and octanucleotide "TATA-box" at around ~-28 bp upstream. Thus, the 3D structure of core promoters of lncRNA resembles the architecture of the core promoters of mRNAs; however, textual analysis revealed differences between promoters of lncRNAs and promoters of mRNAs, which lies in their textual characteristics; namely, the informational entropy at each position of the nucleotide text of lncRNA core promoters (by the exception of singular regions) is significantly higher than that of the mRNA core promoters. Another distinguishing feature of lncRNA is the extremely rare occurrence in the TATA box of octanucleotides with the consensus sequence. These textual differences can significantly affect the efficiency of the transcription of lncRNAs.

Recessive embryonic lethal mutations uncovered in heterozygous condition in silkworm semiconsomic strains.

In this study, we found two embryonic lethal mutations, t04 lethal (l-t04) and m04 lethal (l-m04), in semiconsomic strains T04 and M04, respectively. In these semiconsomic strains, the entire diploid genome, except for one chromosome 4 of the wild silkworm Bombyx mandarina, is substituted with chromosomes of the domesticated silkworm B. mori, and l-t04 and l-m04 mutations are located on B. mandarina-derived chromosome 4. To clarify the cause of the lethalities and the genes responsible for these mutations, positional cloning and CRISPR/Cas9 mediated knockout screening were performed. Finally, genetic complementation tests identified the mutations responsible for the l-t04 and l-m04 as the Bombyx homolog of imaginal discs arrested (Bmida) and TATA box binding protein-associated factor 5 (BmTaf5), respectively. Lethal stages of each knockout mutant indicated the importance of these genes in B. mori late embryogenesis. The lethal mutations responsible for l-t04 and l-m04 were not found in parental strains or wild B. mandarina collected from 39 distinct locations in Japan, indicating that both mutations were independently introduced during or after the development of the semiconsomic strains. We conclude that the recessive embryonic lethality in the T04 and M04 strains is due to deleterious mutations produced in B. mandarina-derived chromosome 4.

On the Role of TATA Boxes and TATA-Binding Protein in Arabidopsis thaliana.

For transcription initiation by RNA polymerase II (Pol II), all eukaryotes require assembly of basal transcription machinery on the core promoter, a region located approximately in the locus spanning a transcription start site (-50; +50 bp). Although Pol II is a complex multi-subunit enzyme conserved among all eukaryotes, it cannot initiate transcription without the participation of many other proteins. Transcription initiation on TATA-containing promoters requires the assembly of the preinitiation complex; this process is triggered by an interaction of TATA-binding protein (TBP, a component of the general transcription factor TFIID (transcription factor II D)) with a TATA box. The interaction of TBP with various TATA boxes in plants, in particular Arabidopsis thaliana, has hardly been investigated, except for a few early studies that addressed the role of a TATA box and substitutions in it in plant transcription systems. This is despite the fact that the interaction of TBP with TATA boxes and their variants can be used to regulate transcription. In this review, we examine the roles of some general transcription factors in the assembly of the basal transcription complex, as well as functions of TATA boxes of the model plant A. thaliana. We review examples showing not only the involvement of TATA boxes in the initiation of transcription machinery assembly but also their indirect participation in plant adaptation to environmental conditions in responses to light and other phenomena. Examples of an influence of the expression levels of A. thaliana TBP1 and TBP2 on morphological traits of the plants are also examined. We summarize available functional data on these two early players that trigger the assembly of transcription machinery. This information will deepen the understanding of the mechanisms underlying transcription by Pol II in plants and will help to utilize the functions of the interaction of TBP with TATA boxes in practice.

Tuning the Transcriptional Activity of the CaMV 35S Promoter in Plants by Single-Nucleotide Changes in the TATA Box.

Synthetic biology uses genetically encoded devices and circuits to implement novel complex functions in living cells and organisms. A hallmark of these genetic circuits is the interaction among their individual parts, according to predefined rules, to process cellular information and produce a circuit output or response. As the number of individual components in a genetic circuit increases, so does the number of interactions needed to achieve the correct behavior, and hence, a greater need to fine-tune the levels of expression of each component. Transcriptional promoters play a key regulatory role in genetic circuits, as they influence the levels of RNA and proteins produced. In multicellular organisms, such as plants, they can also determine developmental, spatial, and tissue-specific patterns of gene expression. The 35S promoter from the Cauliflower Mosaic Virus (CaMV 35S) is widely used in plant biotechnology to direct high levels of gene expression in a variety of plant species. We produced a library of 21 variants of the CaMV 35S promoter by introducing all single nucleotide substitutions to the promoter's TATA box sequence. We then characterized the activity of all variants in homozygous transgenic plants and showed that some of these variants have lower activity than the wild type in plants. These promoter variants could be used to fine-tune the behavior of synthetic genetic circuits in plants.

Human_SNP_TATAdb: a database of SNPs that statistically significantly change the affinity of the TATA-binding protein to human gene promoters: genome-wide analysis and use cases.

It was previously shown that the expression levels of human genes positively correlate with TBP affinity for the promoters of these genes. In turn, single nucleotide polymorphisms (SNPs) in human gene promoters can affect TBP affinity for DNA and, as a consequence, gene expression. The Institute of Cytology and Genetics SB RAS (ICG) has developed a method for predicting TBP affinity for gene promoters based on a three-step binding mecha- nism: (1) TBP slides along DNA, (2) TBP stops at the binding site, and (3) the TBP-promoter complex is fixed due to DNA helix bending. The method showed a high correlation of theoretical predictions with measured values during repeated experimental testing by independent groups of researchers. This model served as a base for other ICG web services, SNP_TATA_Z-tester and SNP_TATA_Comparator, which make a statistical assessment of the SNP-induced change in the affinity of TBP binding to the human gene promoter and help predict changes in expression that may be associated with a genetic predisposition to diseases or phenotypic features of the organism. In this work, we integrated into a single database information about SNPs in human gene promoters obtained by automatic extrac- tion from various heterogeneous data sources, as well as the estimates of TBP affinity for the promoter obtained using the three-step binding model and predicting their effect on gene expression for wild-type promoters and promoters with SNPs. We have shown that Human_SNP_TATAdb can be used for annotation and identification of candidate SNP markers of diseases. The results of a genome-wide data analysis are presented, including the distri- bution of genes with respect to the number of transcripts, the distribution of SNPs affecting TBP-DNA affinity with respect to positions within promoters, as well as patterns linking TBP affinity for the promoter, the specificity of the TBP binding site for the promoter and other characteristics of promoters. The results of the genome-wide analysis showed that the affinity of TBP for the promoter and the specificity of its binding site are statistically related to other characteristics of promoters important for the functional classification of promoters and the study of the features of differential gene expression.

iPromoter-Seqvec: identifying promoters using bidirectional long short-term memory and sequence-embedded features.

BACKGROUND: Promoters, non-coding DNA sequences located at upstream regions of the transcription start site of genes/gene clusters, are essential regulatory elements for the initiation and regulation of transcriptional processes. Furthermore, identifying promoters in DNA sequences and genomes significantly contributes to discovering entire structures of genes of interest. Therefore, exploration of promoter regions is one of the most imperative topics in molecular genetics and biology. Besides experimental techniques, computational methods have been developed to predict promoters. In this study, we propose iPromoter-Seqvec - an efficient computational model to predict TATA and non-TATA promoters in human and mouse genomes using bidirectional long short-term memory neural networks in combination with sequence-embedded features extracted from input sequences. The promoter and non-promoter sequences were retrieved from the Eukaryotic Promoter database and then were refined to create four benchmark datasets. RESULTS: The area under the receiver operating characteristic curve (AUCROC) and the area under the precision-recall curve (AUCPR) were used as two key metrics to evaluate model performance. Results on independent test sets showed that iPromoter-Seqvec outperformed other state-of-the-art methods with AUCROC values ranging from 0.85 to 0.99 and AUCPR values ranging from 0.86 to 0.99. Models predicting TATA promoters in both species had slightly higher predictive power compared to those predicting non-TATA promoters. With a novel idea of constructing artificial non-promoter sequences based on promoter sequences, our models were able to learn highly specific characteristics discriminating promoters from non-promoters to improve predictive efficiency. CONCLUSIONS: iPromoter-Seqvec is a stable and robust model for predicting both TATA and non-TATA promoters in human and mouse genomes. Our proposed method was also deployed as an online web server with a user-friendly interface to support research communities. Links to our source codes and web server are available at https://github.com/mldlproject/2022-iPromoter-Seqvec .