General Transcription Factor Research Articles

The long transcript of lncRNA TMPO-AS1 promotes bone metastases of prostate cancer by regulating the CSNK2A1/DDX3X complex in Wnt/β-catenin signaling

The second most common male cancer is prostate cancer (PCa), which has a high tendency for bone metastasis. Long non-coding RNAs, including TMPO-AS1, play a crucial role in PCa progression. However, TMPO-AS1’s function in PCa bone metastasis (BM) and its underlying molecular mechanisms are unclear. Herein, we found that the long transcript of TMPO-AS1 (TMPO-AS1L) was upregulated in PCa tissues with bone metastasis, and overexpression of TMPO-AS1L correlated with advanced clinicopathological features and reduced BM-free survival in patients with PCa. Upregulated TMPO-AS1L promoted, whereas downregulated TMPO-AS1L inhibited, the PCa cell bone metastatic capacity in vitro and in vivo. Mechanistically, TMPO-AS1L was demonstrated to act as a scaffold, that strengthened the interaction of casein kinase 2 alpha 1 (CSNK2A1) and DEAD-box helicase 3 X-linked (DDX3X), and activated the Wnt/β-catenin signaling pathway, thus promoting BM of PCa. Moreover, upregulation of TMPO-AS1L in PCa resulted from transcription elongation modulated by general transcription factor IIF subunit 2 (GTF2F2). Collectively, our study provides critical insights into the role of TMPO-AS1L in PCa BM via Wnt/β-catenin signaling, identifying TMPO-AS1L as a candidate marker of PCa bone metastasis prognosis and therapeutic target.

HMG-boxes, ribosomopathies and neurodegenerative disease.

The UBTF E210K neuroregression syndrome is a predominantly neurological disorder caused by recurrent de novo dominant variants in Upstream Binding Factor, that is, essential for transcription of the ribosomal RNA genes. This unusual form of ribosomopathy is characterized by a slow decline in cognition, behavior, and sensorimotor functioning during the critical period of development. UBTF (or UBF) is a multi-HMGB-box protein that acts both as an epigenetic factor to establish "open" chromatin on the ribosomal genes and as a basal transcription factor in their RNA Polymerase I transcription. Here we review the possible mechanistic connections between the UBTF variants, ribosomal RNA gene transcription and the neuroregression syndrome, and suggest that DNA topology may play an important role.

Aberrant accumulation of Kras-dependent pervasive transcripts during tumor progression renders cancer cells dependent on PAF1 expression

KRAS is the most commonly mutated oncogene in human cancer, and mutant KRAS is responsible for over 90% of pancreatic ductal adenocarcinoma (PDAC), the most lethal cancer. Here, we show that RNA polymerase II-associated factor 1 complex (PAF1C) is specifically required for survival of PDAC but not normal adult pancreatic cells. We show that PAF1C maintains cancer cell genomic stability by restraining overaccumulation of enhancer RNAs (eRNAs) and promoter upstream transcripts (PROMPTs) driven by mutant Kras. Loss of PAF1C leads to cancer-specific lengthening and accumulation of pervasive transcripts on chromatin and concomitant aberrant R-loop formation and DNA damage, which, in turn, trigger cell death. We go on to demonstrate that the global transcriptional hyperactivation driven by Kras signaling during tumorigenesis underlies the specific demand for PAF1C by cancer cells. Our work provides insights into how enhancer transcription hyperactivation causes general transcription factor addiction during tumorigenesis.

Disruption of the Mammalian Ccr4-Not Complex Contributes to Transcription-Mediated Genome Instability.

The mammalian Ccr4-Not complex, carbon catabolite repression 4 (Ccr4)-negative on TATA-less (Not), is a large, highly conserved, multifunctional assembly of proteins that acts at different cellular levels to regulate gene expression. It is involved in the control of the cell cycle, chromatin modification, activation and inhibition of transcription initiation, control of transcription elongation, RNA export, and nuclear RNA surveillance; the Ccr4-Not complex also plays a central role in the regulation of mRNA decay. Growing evidence suggests that gene transcription has a vital role in shaping the landscape of genome replication and is also a potent source of replication stress and genome instability. Here, we have examined the effects of the inactivation of the Ccr4-Not complex, via the depletion of the scaffold subunit CNOT1, on DNA replication and genome integrity in mammalian cells. In CNOT1-depleted cells, the elevated expression of the general transcription factor TATA-box binding protein (TBP) leads to increased RNA synthesis, which, together with R-loop accumulation, results in replication fork slowing, DNA damage, and senescence. Furthermore, we have shown that the stability of TBP mRNA increases in the absence of CNOT1, which may explain its elevated protein expression in CNOT1-depleted cells. Finally, we have shown the activation of mitogen-activated protein kinase signalling as evidenced by ERK1/2 phosphorylation in the absence of CNOT1, which may be responsible for the observed cell cycle arrest at the border of G1/S.

Structural polymorphism of the PH domain in TFIIH.

The general transcription factor TFIIH is a multi-subunit complex involved in transcription, DNA repair, and cell cycle in eukaryotes. In the human p62 subunit and the budding yeast Saccharomyces cerevisiae Tfb1 subunit of TFIIH, the pleckstrin homology (PH) domain (hPH/scPH) recruits TFIIH to transcription-start and DNA-damage sites by interacting with an acidic intrinsically disordered region in transcription and repair factors. Whereas metazoan PH domains are highly conserved and adopt a similar structure, fungal PH domains are divergent and only the scPH structure is available. Here, we have determined the structure of the PH domain from Tfb1 of fission yeast Schizosaccharomyces pombe (spPH) by NMR. spPH holds an architecture, including the core and external backbone structures, that is closer to hPH than to scPH despite having higher amino acid sequence identity to scPH. In addition, the predicted target-binding site of spPH shares more amino acid similarity with scPH, but spPH contains several key residues identified in hPH as required for specific binding. Using chemical shift perturbation, we have identified binding modes of spPH to spTfa1, a homologue of hTFIIEα, and to spRhp41, a homologue of the repair factors hXPC and scRad4. Both spTfa1 and spRhp41 bind to a similar but distinct surface of spPH by modes that differ from those of target proteins binding to hPH and scPH, revealing that the PH domain of TFIIH interacts with its target proteins in a polymorphic manner in Metazoa, and budding and fission yeasts.

TATA-box-binding protein promotes hepatocellular carcinoma metastasis through epithelial-mesenchymal transition.

HCC characterizes malignant metastasis with high incidence and recurrence. Thus, it is pivotal to discover the mechanisms of HCC metastasis. TATA-box-binding protein (TBP), a general transcriptional factor (TF), couples with activators and chromatin remodelers to sustain the transcriptional activity of target genes. Here, we investigate the key role of TBP in HCC metastasis. TBP expression was measured by PCR, western blot, and immunohistochemistry. RNA-sequencing was performed to identify downstream proteins. Functional assays of TBP and downstream targets were identified in HCC cell lines and xenograft models. Luciferase reporter and chromatin immunoprecipitation assays were used to demonstrate the mechanism mediated by TBP. HCC patients showed high expression of TBP, which correlated with poor prognosis. Upregulation of TBP increased HCC metastasis in vivo and in vitro, and muscleblind-like-3 (MBNL3) was the effective factor of TBP, positively related to TBP expression. Mechanically, TBP transactivated and enhanced MBNL3 expression to stimulate exon inclusion of lncRNA-paxillin (PXN)-alternative splicing (AS1) and, thus, activated epithelial-mesenchymal transition for HCC progression through upregulation of PXN. Our data revealed that TBP upregulation is an HCC enhancer mechanism that increases PXN expression to drive epithelial-mesenchymal transition.

M6A mRNA Methylation Analysis Provides Novel Insights into Pigmentation in Sheep Skin

ABSTRACT N6-methyladenosine (m6A) is the most universal post-transcriptional modification of mRNA which may play important roles in verious species. However, the potential roles of m6A in the pigmentation of skin are not completely understood. To explore the role of m6A modification in pigmentation of sheep skin, we used MeRIP-seq and RNA-seq to profile the skin transcriptome in black and white coat color (n=3). Our results showed that an average of 7701 m6A peaks were obtained for all samples and the average length was 305.89 bp. The GGACUU sequence was the most enrichment motif and shared in black skin and white skin. The m6A peaks were mainly enriched in the CDS, 3'UTR and 5'UTR, especially in CDS region near the stop codon of the transcript. 235 significantly differential peaks were found in black skin vs. white skin. The KEGG signaling pathways of downregulated and upregulated m6A peaks were mainly enriched in AGE-RAGE signaling pathway in diabetic complications, Viral carcinogenesis, Transcriptional misregulation in cancer, ABC transporters, Basal transcription factors and Thyroid hormone synthesis (P value <0.05). For RNA-seq, 71 differently expressed genes (DEGs) were scanned in black skin vs. white skin. DEGs were significantly enriched in tyrosine metabolism, melanogenesis, neuroactive ligand-receptor interaction pathway (P value <0.05). Combined m6A-seq and RNA-seq analysis showed that the hyper-up genes and hypo-up genes were both enriched in ErbB signaling pathway (P value <0.05). In conclusion, it provide a basis for further research into the functions of m6A methylation modifications in pigmentation.

BTF3 promotes proliferation and glycolysis in hepatocellular carcinoma by regulating GLUT1

ABSTRACT Hepatocellular carcinoma (HCC) is a grievous tumor with an increasing incidence worldwide. Basic transcription factor 3 (BTF3) is discovered to regulate the expression of glucose transporter 1 (GLUT1), which benefits glycolysis, a momentous signature of tumors, through transactivation of the forkhead box M1 (FOXM1) expression. BTF3 is highly expressed in HCC. However, whether BTF3 promotes GLUT1 expression through FOXM1 to modulate glycolysis in HCC remains unclear. The expression profile of BTF3 were determined by online database, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot. The role and mechanism of BTF3 in the proliferation and glycolysis of HCC cells were examined by cell counting kit-8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EdU) incorporation, XF96 Extracellular Flux analyzer, spectrophotometry and western blot analysis. In addition, the direct interaction between BTF3 and FOXM1 was verified by dual-luciferase reporter and co-immunoprecipitation assays. Moreover, the role of BTF3 was also explored in a xenografted mice model. The expression of BTF3 was increased in HCC cells and tumor tissues. Knockdown of BTF3 reduced the cell viability, Edu positive cells, extracellular acidification rate (ECAR), glucose consumption and lactate production in both Huh7 and HCCLM3 cells. The expressions of FOXM1 and GLUT1 were increased in HCC tissues, which were positively correlated with the BTF3 expression. Moreover, a direct interaction existed between BTF3 and FOXM1 in HCC cells. Downregulation of BTF3 decreased the relative protein levels of FOXM1 and GLUT1, which were rescued with overexpression of FOXM1 in both cells. More importantly, overexpression of FOXM1 restored the cell viability, ECAR, glucose consumption and lactate production in both Huh7 and HCCLM3 cells transfected with siBTF3#1. Furthermore, inhibition of BTF3 decreased tumor weight and volume, and the relative level of BTF3, FOXM1, GLUT1 and Ki-67 in tumor tissues from mice xenografted with Huh7 cells. BTF3 enhanced the cell proliferation and glycolysis through FOXM1/GLUT1 axis in HCC.

Hierarchical TAF1-dependent co-translational assembly of the basal transcription factor TFIID.

Large heteromeric multiprotein complexes play pivotal roles at every step of gene expression in eukaryotic cells. Among them, the 20-subunit basal transcription factor TFIID nucleates the RNA polymerase II preinitiation complex at gene promoters. Here, by combining systematic RNA-immunoprecipitation (RIP) experiments, single-molecule imaging, proteomics and structure-function analyses, we show that human TFIID biogenesis occurs co-translationally. We discovered that all protein heterodimerization steps happen during protein synthesis. We identify TAF1-the largest protein in the complex-as a critical factor for TFIID assembly. TAF1 acts as a flexible scaffold that drives the co-translational recruitment of TFIID submodules preassembled in the cytoplasm. Altogether, our data suggest a multistep hierarchical model for TFIID biogenesis that culminates with the co-translational assembly of the complex onto the nascent TAF1 polypeptide. We envision that this assembly strategy could be shared with other large heteromeric protein complexes.

Polymorphism of GTF2A1 gene is associated with litter size in sheep

General transcription factor IIA subunit 1 (GTF2A1) is required for transcriptional activation from most promoters in eukaryotic transcription. Previous whole-genome association analyses articles have predicted the effect of this gene on lambing in sheep. In the study, a total of nine insertion/deletion (indel) variants named L1 to L9 in the gene were selected to detect in 550 Australian White sheep (AuW) adult ewes. The polymorphisms were detected in four loci (L1, L2, L3 and L8locus) and the polymorphism information content (PIC) values were 0.270, 0.375, 0.372 and 0.314. Further, our study revealed that L1, L2 and L3 loci of GTF2A1 gene were significantly related to the first parity litter size and the polymorphism of L8 was significantly correlated with litter size in the second parity. In details, for the first parity, individuals with the II genotype of the L1 locus had higher little size than that with the ID genotype, individuals with the ID and DD genotype of the L2 locus had higher little size than that with the II genotype, and individuals with the DD genotype of the L3 locus had higher little size than that with the II genotype. All four loci do not follow to Hardy-Weinberg equilibrium, and have no linkage between them. In conclusion, the polymorphisms of GTF2A1 were confirmed and analysis results demonstrated that there are some relevance between difference genotypes and litter size, and these findings may provide new insights for accelerating sheep molecular breeding through molecular marker-assisted selection (MAS).

Promoter-proximal regulation of gene transcription: Key factors involved and emerging role of general transcription factors in assisting productive elongation

The pausing of RNA polymerase II (Pol II) at the promoter-proximal sites is a key rate-limiting step in gene expression. Cells have dedicated a specific set of proteins that sequentially establish pause and then release the Pol II from promoter-proximal sites. A well-controlled pausing and subsequent release of Pol II is crucial for the fine tuning of expression of genes including signal-responsive and developmentally-regulated ones. The release of paused Pol II broadly involves its transition from initiation to elongation. In this review article, we will discuss the phenomenon of Pol II pausing, the underlying mechanism, and also the role of different known factors, with an emphasis on general transcription factors, involved in this overall regulation. We will further discuss some recent findings suggesting a possible role (underexplored) of initiation factors in assisting the transition of transcriptionally-engaged paused Pol II into productive elongation.

GNPNAT1 is a potential biomarker correlated with immune infiltration and immunotherapy outcome in breast cancer.

Glucosamine 6-phosphate N-acetyltransferase (GNPNAT1) is a crucial enzyme involving hexosamine biosynthesis pathway and is upregulated in breast cancer (BRCA). However, its biological function and mechanism on patients in BRCA have not been investigated. In this study, the differential expression of GNPNAT1 was analyzed between BRCA tissues and normal breast tissues using the Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database, which was validated by quantitative real-time polymerase chain reaction, Western blot and immunohistochemistry. Then, the potential clinical value of GNPNAT1 in BRCA was investigated based on TCGA database. Functional enrichment analyses, including Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Gene Set Variation Analysis, were performed to explore the potential signaling pathways and biological functions involved in GNPNAT1 in BRCA. Tumor immune infiltration was analyzed using ESTIMATE, CIBERSORT and TISIDB database; and immune therapy response scores were assessed using TIDE. Finally, Western blot, Cell counting kit-8 and Transwell assay were used to determine the proliferation and invasion abilities of breast cancer cells with GNPNAT1 knockdown. GNPNAT1 was up-regulated in BRCA tissues compared with normal tissues which was subsequently verified in different cell lines and clinical tissue samples. Based on TCGA and GEO, the overexpression of GNPNAT1 in BRCA contributed to a significant decline in overall survive and disease specific survive. Functional enrichment analyses indicated that the enriched pathways in high GNPNAT1 expression group included citrate cycle, N-glycan biosynthesis, DNA repair, and basal transcription factors. Moreover, the overexpression of GNPNAT1 was negatively correlated with immunotherapy response and the levels of immune cell infiltration of CD8+ T cells, B cells, natural killer cells, dendritic cells and macrophages. Knockdown of GNPNAT1 impairs the proliferation and invasion abilities of breast cancer cells. GNPNAT1 is a potential diagnostic, prognostic biomarker and novel target for intervention in BRCA.

Analysis of basic pentacysteine6 transcription factor involved in abiotic stress response in Arabidopsis thaliana.

Background: Abiotic stress is a significant environmental factor that limits plant growth. Plants have complex and diverse mechanisms for dealing with abiotic stress, and different response mechanisms are interconnected. Our research aims to find key transcription factors that can respond to multiple non -biological stress. Methods: We used gene expression profile data of Arabidopsis in response to abiotic stress, constructed a weighted gene co-expression network, to obtain key modules in the network. The functions and pathways involved in these modules were further explored by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Through the enrichment analysis of transcription factor, the transcription factor that plays an important regulatory role in the key module. Through gene difference expression analysis and building protein interaction networks, the important role of key transcription factors is verified. Result: In weighted gene co-expression network, identified three gene modules that are primarily associated with cold stress, heat stress, and salt stress. Functional enrichment analysis indicated that the genes in these modules participate in biological processes such as protein binding, stress response, and others. Transcription factor enrichment analysis revealed that the transcription factor Basic Pentacysteine6 (BPC6) plays a crucial regulatory role in these three modules. The expression of the BPC6 gene is dramatically affected under a variety of abiotic stress treatments, according to an analysis of Arabidopsis gene expression data under abiotic stress treatments. Differential expression analysis showed that there were 57 differentially expressed genes in bpc4 bpc6 double mutant Arabidopsis relative to normal Arabidopsis samples, including 14 BPC6 target genes. Protein interaction network analysis indicated that the differentially expressed genes had strong interactions with BPC6 target genes within the key modules. Conclusion: Our findings reveal that the BPC6 transcription factor plays a key regulatory function in Arabidopsis coping with a variety of abiotic stresses, which opens up new ideas and perspectives for us to understand the mechanism of plants coping with abiotic stresses.

Adaption of Pseudomonas ogarae F113 to the Rhizosphere Environment-The AmrZ-FleQ Hub.

Motility and biofilm formation are two crucial traits in the process of rhizosphere colonization by pseudomonads. The regulation of both traits requires a complex signaling network that is coordinated by the AmrZ-FleQ hub. In this review, we describe the role of this hub in the adaption to the rhizosphere. The study of the direct regulon of AmrZ and the phenotypic analyses of an amrZ mutant in Pseudomonas ogarae F113 has shown that this protein plays a crucial role in the regulation of several cellular functions, including motility, biofilm formation, iron homeostasis, and bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) turnover, controlling the synthesis of extracellular matrix components. On the other hand, FleQ is the master regulator of flagellar synthesis in P. ogarae F113 and other pseudomonads, but its implication in the regulation of multiple traits related with environmental adaption has been shown. Genomic scale studies (ChIP-Seq and RNA-Seq) have shown that in P. ogarae F113, AmrZ and FleQ are general transcription factors that regulate multiple traits. It has also been shown that there is a common regulon shared by the two transcription factors. Moreover, these studies have shown that AmrZ and FleQ form a regulatory hub that inversely regulate traits such as motility, extracellular matrix component production, and iron homeostasis. The messenger molecule c-di-GMP plays an essential role in this hub since its production is regulated by AmrZ and it is sensed by FleQ and required for its regulatory role. This regulatory hub is functional both in culture and in the rhizosphere, indicating that the AmrZ-FleQ hub is a main player of P. ogarae F113 adaption to the rhizosphere environment.

The SmNPR4-SmTGA5 module regulates SA-mediated phenolic acid biosynthesis in Salvia miltiorrhiza hairy roots.

Phenolic acids are the main bioactive compounds in Salvia miltiorrhiza, which can be increased by salicylic acid (SA) elicitation. However, the specific molecular mechanism remains unclear. The nonexpresser of PR genes 1 (NPR1) and its family members are essential components of the SA signaling pathway. Here, we report an NPR protein, SmNPR4, that showed strong expression in hairy root after SA treatment, acting as a negative moderator of SA-induced phenolic acid biosynthesis in S. miltiorrhiza (S. miltiorrhiza). Moreover, a basic leucine zipper family transcription factor SmTGA5 was identified and was found to interact with SmNPR4. SmTGA5 activates the expression of phenolic acid biosynthesis gene SmTAT1 through binding to the as-1 element. Finally, a series of biochemical assays and dual gene overexpression analysis demonstrated that the SmNPR4 significantly inhibited the function of SmTGA5, and SA can alleviate the inhibitory effect of SmNPR4 on SmTGA5. Overall, our results reveal the molecular mechanism of salicylic acid regulating phenolic acid biosynthesis in S. miltiorrhiza and provide new insights for SA signaling to regulate secondary metabolic biosynthesis.

Genetic profile of thymic epithelial tumors in the Japanese population: an exploratory study examining potential therapeutic targets.

Thymic epithelial tumors (TETs) are prone to developing in East Asian populations. However, little is known about the genomic profile of TETs in East Asian populations, and the genomic aberrations in TETs have not yet been fully clarified. Thus, molecular targeted therapies for patients with TETs have not been established. This prospective study was conducted to explore the genetic abnormalities of surgically resected TETs in a Japanese cohort and to identify clues for carcinogenesis and potential therapeutic targets in TETs. Genetic profiles of TETs were investigated using fresh-frozen specimens resected from operable cases with TETs. DNA sequencing was performed using a next-generation sequencing (NGS) gene panel test with Ion Reporter™ and CLC Genomics Workbench 11.0. The mutation sites were further confirmed by Sanger sequencing, digital droplet polymerase chain reaction (ddPCR), and TA cloning for validation. Among 43 patients diagnosed with anterior mediastinal tumors between January 2013 and March 2019, NGS and validation analyses were performed in 31 patients [29 thymomas and two thymic cancers (TCs)] who met the study criteria. Of these, 12 cases of thymoma types A, AB, B1, and B2 harbored the general transcription factor 2-I (GTF2I) mutation (L424H). Conversely, the mutation was not detected in type B3 thymoma or TC, suggesting that the GTF2I mutation existed in indolent types of TETs. Rat sarcoma viral oncogene (RAS) mutations were detected in three cases [Harvey RAS (HRAS) in two cases of type AB thymoma and neuroblastoma RAS (NRAS)] in one case of type B1 thymoma), and additional sex combs like 1 (ASXL1) mutation was present in one case of TC. All RAS mutations were observed in GTF2I-mutated cases. The GTF2I mutation (L424H) is the most frequently occurring mutation in the limited histology of thymoma, consistent with those in the non-Asian population. HRAS and NRAS mutations co-occurred in cases harboring the GTF2I mutation. These findings suggest that the existence of the GTF2I mutation might be related to indolent types of TETs, and RAS mutations could be candidates as therapeutic targets in TETs.

Identification of a peptide ligand for human ALDH3A1 through peptide phage display: Prediction and characterization of protein interaction sites and inhibition of ALDH3A1 enzymatic activity.

Aldehyde dehydrogenase 3A1 (ALDH3A1) by oxidizing medium chain aldehydes to their corresponding carboxylic acids, is involved in the detoxification of toxic byproducts and is considered to play an important role in antioxidant cellular defense. ALDH3A1 has been implicated in various other functions such as cell proliferation, cell cycle regulation, and DNA damage response. Recently, it has been identified as a putative biomarker of prostate, gastric, and lung cancer stem cell phenotype. Although ALDH3A1 has multifaceted functions in both normal and cancer homeostasis, its modes of action are currently unknown. To this end, we utilized a random 12-mer peptide phage display library to identify efficiently human ALDH3A1-interacting peptides. One prevailing peptide (P1) was systematically demonstrated to interact with the protein of interest, which was further validated in vitro by peptide ELISA. Bioinformatic analysis indicated two putative P1 binding sites on the protein surface implying biomedical potential and potent inhibitory activity of the P1 peptide on hALDH3A1 activity was demonstrated by enzymatic studies. Furthermore, in search of potential hALDH3A1 interacting players, a BLASTp search demonstrated that no protein in the database includes the full-length amino acid sequence of P1, but identified a list of proteins containing parts of the P1 sequence, which may prove potential hALDH3A1 interacting partners. Among them, Protein Kinase C Binding Protein 1 and General Transcription Factor II-I are candidates of high interest due to their cellular localization and function. To conclude, this study identifies a novel peptide with potential biomedical applications and further suggests a list of protein candidates be explored as possible hALDH3A1-interacting partners in future studies.

Multimolecular characteristics and role of BRCA1 interacting protein C-terminal helicase 1 (BRIP1) in human tumors: a pan-cancer analysis

BackgroundThe aberrant expression of BRIP1 was associated with several cancers; however, the panoramic picture of BRIP1 in human tumors remains unclear. This study aims to explore the pan-cancerous picture of the expression of BRIP1 across 33 human cancers.MethodsBased on the data from TCGA and GTEx, a series of bioinformatic analyses were applied to systematically explore the genetic landscape and biologic function of BRIP1 in 33 human tumors.ResultsWe observed prognosis-related differential BRIP1 expressions between various carcinomas and the corresponding normal tissues. “Basal transcription factors,” “homologous recombination,” “nucleotide excision repair,” and DNA metabolism pathways may play a role in the functional mechanisms of BRIP1. Patients with uterine corpus endometrial carcinoma presented with the highest alteration frequency of BRIP1 (nearly 10%). Single-nucleotide and copy number variations of BRIP1 were noticed in multiple cancers, and the expression of BRIP1 is significantly regulated by copy number variation in breast invasive carcinoma and lung squamous cell carcinoma. BRIP1 expression is negatively correlated with the DNA methylation levels in many tumors and is associated with the activation of apoptosis, cell cycle, DNA damage response, and inhibition of hormone ER and RNS/MARK signaling pathways. Moreover, a positive correlation was observed between BRIP1 expression and the immune infiltration levels of cancer-associated fibroblasts and CD8+ T cells in lung adenocarcinoma.ConclusionOur pan-cancer analysis of BRIP1 provides a valuable resource for understanding the multimolecular characteristics and biological function of BRIP1 across human cancers.

R3-MYB repressor Mybr97 is a candidate gene associated with the Anthocyanin3 locus and enhanced anthocyanin accumulation in maize.

Anthocyanin3 inhibits the anthocyanin and monolignol pathways in maize. Transposon-tagging, RNA-sequencing, and GST-pulldown assays determine Anthocyanin3 may be R3-MYB repressor gene Mybr97. Anthocyanins are colorful molecules receiving recent attention due to their numerous health benefits and applications as natural colorants and nutraceuticals. Purple corn is being investigated as a more economical source of anthocyanins. Anthocyanin3 (A3) is a known recessive intensifier of anthocyanin pigmentation in maize. In this study, anthocyanin content was elevated 100-fold in recessive a3 plants. Two approaches were used to discover candidates involved with the a3 intense purple plant phenotype. First, a large-scale transposon-tagging population was created with a Dissociation (Ds) insertion in the nearby Anthocyanin1 gene. A de novo a3-m1::Ds mutant was generated, and the transposon insertion was found to be located in the promoter of Mybr97, which has homology to R3-MYB repressor CAPRICE in Arabidopsis. Second, a bulked segregant RNA-sequencing population found expression differences between pools of green A3 plants and purple a3 plants. All characterized anthocyanin biosynthetic genes were upregulated in a3 plants along with several genes of the monolignol pathway. Mybr97 was highly downregulated in a3 plants, suggesting its role as a negative regulator of the anthocyanin pathway. Photosynthesis-related gene expression was reduced in a3 plants through an unknown mechanism. Numerous transcription factors and biosynthetic genes were also upregulated and need further investigation. Mybr97 may inhibit anthocyanin synthesis by associating with basic helix-loop helix transcription factors like Booster1. Overall, Mybr97 is the most likely candidate gene for the A3 locus. A3 has a profound effect on the maize plant and has many favorable implications for crop protection, human health, and natural colorant production.

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.