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International Journal of Molecular... Jun 2021Plants face a more volatile environment than other organisms because of their immobility, and they have developed highly efficient mechanisms to adapt to stress... (Review)
Review
Plants face a more volatile environment than other organisms because of their immobility, and they have developed highly efficient mechanisms to adapt to stress conditions. Transcription factors, as an important part of the adaptation process, are activated by different signals and are responsible for the expression of stress-responsive genes. MYB transcription factors, as one of the most widespread transcription factor families in plants, participate in plant development and responses to stresses by combining with MYB -elements in promoters of target genes. MYB transcription factors have been extensively studied and have proven to be critical in the biosynthesis of secondary metabolites in plants, including anthocyanins, flavonols, and lignin. Multiple studies have now shown that MYB proteins play diverse roles in the responses to abiotic stresses, such as drought, salt, and cold stresses. However, the regulatory mechanism of MYB proteins in abiotic stresses is still not well understood. In this review, we will focus mainly on the function of MYB transcription factors in abiotic stresses, especially how MYB proteins participate in these stress responses. We also pay attention to how the MYB proteins are regulated in these processes at both the transcript and protein levels.
Topics: Arabidopsis; Arabidopsis Proteins; Droughts; Gene Expression Regulation, Plant; Stress, Physiological; Transcription Factors
PubMed: 34200125
DOI: 10.3390/ijms22116125 -
International Journal of Molecular... Jul 2021The basic helix-loop-helix (bHLH) transcription factor family is one of the largest transcription factor gene families in Arabidopsis thaliana, and contains a bHLH motif... (Review)
Review
The basic helix-loop-helix (bHLH) transcription factor family is one of the largest transcription factor gene families in Arabidopsis thaliana, and contains a bHLH motif that is highly conserved throughout eukaryotic organisms. Members of this family have two conserved motifs, a basic DNA binding region and a helix-loop-helix (HLH) region. These proteins containing bHLH domain usually act as homo- or heterodimers to regulate the expression of their target genes, which are involved in many physiological processes and have a broad range of functions in biosynthesis, metabolism and transduction of plant hormones. Although there are a number of articles on different aspects to provide detailed information on this family in plants, an overall summary is not available. In this review, we summarize various aspects of related studies that provide an overview of insights into the pleiotropic regulatory roles of these transcription factors in plant growth and development, stress response, biochemical functions and the web of signaling networks. We then provide an overview of the functional profile of the bHLH family and the regulatory mechanisms of other proteins.
Topics: Amino Acid Sequence; Arabidopsis; Arabidopsis Proteins; Basic Helix-Loop-Helix Transcription Factors; Gene Expression; Genome, Plant; Helix-Loop-Helix Motifs; Multigene Family; Phylogeny; Plant Proteins; Sequence Analysis, DNA; Transcription Factors
PubMed: 34281206
DOI: 10.3390/ijms22137152 -
Molecular Cell May 2023The prevailing view of metazoan gene regulation is that transcription is facilitated through the formation of static activator complexes at distal regulatory regions....
The prevailing view of metazoan gene regulation is that transcription is facilitated through the formation of static activator complexes at distal regulatory regions. Here, we employed quantitative single-cell live-imaging and computational analysis to provide evidence that the dynamic assembly and disassembly process of transcription factor (TF) clusters at enhancers is a major source of transcriptional bursting in developing Drosophila embryos. We further show that the regulatory connectivity between TF clustering and burst induction is highly regulated through intrinsically disordered regions (IDRs). Addition of a poly-glutamine tract to the maternal morphogen Bicoid demonstrated that extended IDR length leads to ectopic TF clustering and burst induction from its endogenous target genes, resulting in defects in body segmentation during embryogenesis. Moreover, we successfully visualized the presence of "shared" TF clusters during the co-activation of two distant genes, which provides a concrete molecular explanation for the newly proposed "topological operon" hypothesis in metazoan gene regulation.
Topics: Animals; Transcription Factors; Drosophila Proteins; Enhancer Elements, Genetic; Gene Expression Regulation, Developmental; Drosophila
PubMed: 37207625
DOI: 10.1016/j.molcel.2023.04.018 -
EBioMedicine Dec 2022The E2F family of transcription factors play a crucial role in the development of various cancers. However, E2F members lack targetable binding pockets and are typically...
BACKGROUND
The E2F family of transcription factors play a crucial role in the development of various cancers. However, E2F members lack targetable binding pockets and are typically considered "undruggable". Unlike canonical small-molecule therapeutics, molecular glues mediate new E3 ligase-protein interactions to induce selective proteasomal degradation, which represents an attractive option to overcome these limitations.
METHODS
Human proteome microarray was utilized to identify a natural product-derived molecular glue for targeting E2F2 degradation. Co-IP analysis with stable isotope labeling of amino acids in cell culture (SILAC)-based quantitative proteomics was carried out to further explore the E3 ligase for E2F2 degradation.
FINDINGS
In this study, we identified a molecular glue bufalin, which significantly promoted E2F2 degradation. Unexpectedly, E2F2 underwent ubiquitination and proteasomal degradation via a previously undisclosed atypical E3 ligase, zinc finger protein 91 (ZFP91). In particular, we observed that bufalin markedly promoted E2F2-ZFP91 complex formation, thereby leading to E2F2 polyubiquitination via K48-linked ubiquitin chains for degradation. E2F2 degradation subsequently caused transcriptional suppression of multiple oncogenes including c-Myc, CCNE1, CCNE2, MCM5 and CDK1, and inhibited hepatocellular carcinoma growth in vitro and in vivo.
INTERPRETATION
Collectively, our findings open up a new direction for transcription factors degradation by targeting atypical E3 ligase ZFP91. Meanwhile, the chemical knockdown strategy with molecular glue may promote innovative transcription factor degrader development in cancer therapy.
FUNDING
This work was financially supported by the National Key Research and Development Project of China (2022YFC3501601), National Natural Sciences Foundation of China (81973505, 82174008, 82030114), and China Postdoctoral Science Foundation (2019M650396), the Fundamental Research Funds for the Central Universities.
Topics: Humans; E2F2 Transcription Factor; Neoplasms; Proteolysis; Transcription Factors; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 36375317
DOI: 10.1016/j.ebiom.2022.104353 -
Journal of Translational Medicine Mar 2023Diabetic nephropathy (DN) is a main cause of chronic renal failure. Despite decades of extensive study, the molecular mechanisms underlying diabetic tubulointerstitial...
BACKGROUND
Diabetic nephropathy (DN) is a main cause of chronic renal failure. Despite decades of extensive study, the molecular mechanisms underlying diabetic tubulointerstitial injury remain unclear. We aim to identify key transcription factor genes involved in diabetic tubulointerstitial injury.
METHODS
A microarray dataset (GSE30122) from Gene Expression Omnibus (GEO) was downloaded. A total of 38 transcription factor genes based on 166 differentially expressed genes (DEGs) were identified by UCSC_TFBS.
RESULTS
The regulatory network showed connections between the top 10 transcription factors and their target DEGs. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of targeted DEGs indicated that extracellular space, extracellular exosome, cell surface and complement and coagulation cascades were most significantly enriched. Utilizing Nephroseq v5 online platform, the mRNA expression pattern analysis of transcription factor genes demonstrated that mRNA expression of CDC5, CEBPA, FAC1, HFH1, IRF1, NFE2 and TGIF1 increased in renal tubulointerstitium of DN patients compared with normal controls while that of CEBPB and FOXO4 decreased in renal tubulointerstitium of DN patients compared with normal controls. Correlation analysis between mRNA expression of transcription factor genes in renal tubulointerstitium and clinical features showed that AP1, BACH1, CDC5, FAC1, FOXD1, FOXJ2, FOXO1, FOXO4, HFH1, IRF1, POU3F2, SOX5, SOX9, RSRFC4, S8 and TGIF1 may be related to diabetic tubulointerstitial injury.
CONCLUSIONS
(1) CDC5, FAC1, FOXO4, HFH1, IRF1 and TGIF1 may be key transcription factor genes. (2)Transcription factors involved in diabetic tubulointerstitial injury may become prospective targets for diagnosis and treatment of DN.
Topics: Humans; Transcription Factors; Gene Expression Profiling; Diabetic Nephropathies; Microarray Analysis; RNA, Messenger; Computational Biology; Gene Regulatory Networks; Diabetes Mellitus; Forkhead Transcription Factors; Repressor Proteins; Homeodomain Proteins
PubMed: 36978091
DOI: 10.1186/s12967-023-04069-8 -
Molecular Cell May 2022Transcription factors (TFs) consist of a DNA-binding domain and an activation domain (AD) that are frequently considered to be independent and exchangeable modules....
Transcription factors (TFs) consist of a DNA-binding domain and an activation domain (AD) that are frequently considered to be independent and exchangeable modules. However, recent studies report that the physicochemical properties of the AD can control TF assembly at chromatin by driving phase separation into transcriptional condensates. Here, we dissected transcription activation by comparing different synthetic TFs at a reporter gene array with real-time single-cell fluorescence microscopy. In these experiments, binding site occupancy, residence time, and coactivator recruitment in relation to multivalent TF interactions were compared. While phase separation propensity and activation strength of the AD were linked, the actual formation of liquid-like TF droplets had a neutral or inhibitory effect on transcription activation. We conclude that multivalent AD-mediated interactions enhance the transcription activation capacity of a TF by increasing its residence time in the chromatin-bound state and facilitating the recruitment of coactivators independent of phase separation.
Topics: Binding Sites; Chromatin; Protein Domains; Transcription Factors; Transcriptional Activation
PubMed: 35537448
DOI: 10.1016/j.molcel.2022.04.017 -
BMC Plant Biology Jun 2019NAC (NAM, ATAF and CUC) transcriptional factors constitute a large family with more than 150 members in rice and several members of this family have been demonstrated to...
BACKGROUND
NAC (NAM, ATAF and CUC) transcriptional factors constitute a large family with more than 150 members in rice and several members of this family have been demonstrated to play crucial roles in rice abiotic stress response. In the present study, we report the function of a novel stress-responsive NAC gene, ONAC066, in rice drought and oxidative stress tolerance.
RESULTS
ONAC066 was localized in nuclei of cells when transiently expressed in Nicotiana benthamiana and is a transcription activator with the binding ability to NAC recognition sequence (NACRS) and AtJUB1 binding site (JBS). Expression of ONAC066 was significantly induced by PEG, NaCl, HO and abscisic acid (ABA). Overexpression of ONAC066 in transgenic rice improved drought and oxidative stress tolerance and increased ABA sensitivity, accompanied with decreased rate of water loss, increased contents of proline and soluble sugars, decreased accumulation of reactive oxygen species (ROS) and upregulated expression of stress-related genes under drought stress condition. By contrast, RNAi-mediated suppression of ONAC066 attenuated drought and oxidative stress tolerance and decreased ABA sensitivity, accompanied with increased rate of water loss, decreased contents of proline and soluble sugars, elevated accumulation of ROS and downregulated expression of stress-related genes under drought stress condition. Furthermore, yeast one hybrid and chromatin immunoprecipitation-PCR analyses revealed that ONAC066 bound directly to a JBS-like cis-elements in OsDREB2A promoter and activated the transcription of OsDREB2A.
CONCLUSION
ONAC066 is a nucleus-localized transcription activator that can respond to multiple abiotic stress factors. Functional analyses using overexpression and RNAi-mediated suppression transgenic lines demonstrate that ONAC066 is a positive regulator of drought and oxidative stress tolerance in rice.
Topics: Droughts; Oryza; Oxidative Stress; Plant Proteins; Sequence Analysis, DNA; Stress, Physiological; Transcription Factors
PubMed: 31238869
DOI: 10.1186/s12870-019-1883-y -
Nucleus (Austin, Tex.) Dec 2023Transcription Factor (TF) condensates are a heterogenous mix of RNA, DNA, and multiple co-factor proteins capable of modulating the transcriptional response of the cell.... (Review)
Review
Transcription Factor (TF) condensates are a heterogenous mix of RNA, DNA, and multiple co-factor proteins capable of modulating the transcriptional response of the cell. The dynamic nature and the spatial location of TF-condensates in the 3D nuclear space is believed to provide a fast response, which is on the same pace as the signaling cascade and yet ever-so-specific in the crowded environment of the nucleus. However, the current understanding of how TF-condensates can achieve these feet so quickly and efficiently is still unclear. In this review, we draw parallels with other protein condensates and share our speculations on how the nucleus uses these TF-condensates to achieve high transcriptional specificity and fidelity. We discuss the various constituents of TF-condensates, their properties, and the known and unknown functions of TF-condensates with a particular focus on steroid signaling-induced transcriptional programs.
Topics: Transcription Factors; DNA; Cell Nucleus; Signal Transduction; Chromatin
PubMed: 37129580
DOI: 10.1080/19491034.2023.2205758 -
Genes & DevelopmentTranscription factors are defined by their sequence-specific binding to DNA and by their selective impacts on gene expression, depending on specific binding sites. The... (Review)
Review
Transcription factors are defined by their sequence-specific binding to DNA and by their selective impacts on gene expression, depending on specific binding sites. The factor binding motifs in the DNA should thus represent a blueprint of regulatory logic, suggesting that transcription factor binding patterns on the genome (e.g., measured by ChIP-seq) should indicate which target genes the factors are directly controlling. However, although genetic data confirm high impacts of transcription factor perturbation in embryology, transcription factors bind to far more sites than the number of genes they dynamically regulate, when measured by direct perturbation in a given cell type. Also, deletion of carefully chosen transcription factor binding sites often gives disappointingly weak results. In a new study in the previous issue of , Lo and colleagues (pp. 1079-1095) reconcile these contradictions by using an elegant experimental system to directly compare the roles of transcription factor-binding site interaction in gene regulation maintenance with roles of the same factor-site interactions in gene regulation through developmental change. They examine Oct4:Sox2 shared target genes under maintained versus reinduced pluripotency conditions within the same cell clone. The results show that the same factor-site interaction impacts can appear modest in assays in developmental steady-state but are far more important as regulatory catalysts of developmental change.
Topics: Transcription Factors; Embryonic Stem Cells; Gene Expression Regulation; Binding Sites; Octamer Transcription Factor-3; DNA; SOXB1 Transcription Factors; Cell Differentiation
PubMed: 36622807
DOI: 10.1101/gad.350308.122 -
Frontiers in Immunology 2023Transcription factors bind promoter or regulatory sequences of a gene to regulate its rate of transcription. However, they are also detected in anucleated platelets. The... (Review)
Review
Transcription factors bind promoter or regulatory sequences of a gene to regulate its rate of transcription. However, they are also detected in anucleated platelets. The transcription factors RUNX1, GATA1, STAT3, NFκB, and PPAR have been widely reported to play key roles in the pathophysiology of platelet hyper-reactivity, thrombosis, and atherosclerosis. These non-transcriptional activities are independent of gene transcription or protein synthesis but their underlying mechanisms of action remain poorly defined. Genetic and acquired defects in these transcription factors are associated with the production of platelet microvesicles that are known to initiate and propagate coagulation and to promote thrombosis. In this review, we summarize recent developments in the study of transcription factors in platelet generation, reactivity, and production of microvesicles, with a focus on non-transcriptional activities of selected transcription factors.
Topics: Humans; Megakaryocytes; Transcription Factors; Blood Platelets; Platelet Count; Thrombosis
PubMed: 36969155
DOI: 10.3389/fimmu.2023.1140501