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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 -
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 -
Cell Jan 2017Oct4, Sox2, Klf4, and cMyc (OSKM) reprogram somatic cells to pluripotency. To gain a mechanistic understanding of their function, we mapped OSKM-binding, stage-specific...
Oct4, Sox2, Klf4, and cMyc (OSKM) reprogram somatic cells to pluripotency. To gain a mechanistic understanding of their function, we mapped OSKM-binding, stage-specific transcription factors (TFs), and chromatin states in discrete reprogramming stages and performed loss- and gain-of-function experiments. We found that OSK predominantly bind active somatic enhancers early in reprogramming and immediately initiate their inactivation genome-wide by inducing the redistribution of somatic TFs away from somatic enhancers to sites elsewhere engaged by OSK, recruiting Hdac1, and repressing the somatic TF Fra1. Pluripotency enhancer selection is a stepwise process that also begins early in reprogramming through collaborative binding of OSK at sites with high OSK-motif density. Most pluripotency enhancers are selected later in the process and require OS and other pluripotency TFs. Somatic and pluripotency TFs modulate reprogramming efficiency when overexpressed by altering OSK targeting, somatic-enhancer inactivation, and pluripotency enhancer selection. Together, our data indicate that collaborative interactions among OSK and with stage-specific TFs direct both somatic-enhancer inactivation and pluripotency-enhancer selection to drive reprogramming.
Topics: Animals; Cellular Reprogramming; Chromatin; Fibroblasts; Histone Code; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Mice; Octamer Transcription Factor-3; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-myc; Regulatory Elements, Transcriptional; SOXB1 Transcription Factors; Silencer Elements, Transcriptional; Transcription Factors
PubMed: 28111071
DOI: 10.1016/j.cell.2016.12.016 -
Journal of Immunological Methods Mar 2016Engagement of the T cell receptor complex reprograms T cells for proliferation, cytokine production and differentiation towards effector cells. This process depends on...
Engagement of the T cell receptor complex reprograms T cells for proliferation, cytokine production and differentiation towards effector cells. This process depends on activating costimulatory signals and is counteracted by coinhibitory molecules. Three transcription factors, namely NF-κB, NFAT and AP-1, have a major role in inducing the transcriptional program that is required for T cell activation and differentiation. Here we describe the generation of a triple parameter reporter based on the human Jurkat T cell line, where response elements for NF-κB, NFAT and AP-1 drive the expression of the fluorescent proteins CFP, eGFP and mCherry, respectively. The emission spectra of these proteins allow simultaneous assessment of NF-κB, NFAT and AP-1 activity in response to stimulation. Ligation of the TCR complex induced moderate reporter activity, which was strongly enhanced upon coengagement of the costimulatory receptors CD2 or CD28. Moreover, we have generated and tested triple parameter reporter cells that harbor costimulatory and inhibitory receptors not endogenously expressed in the Jurkat cells. In these experiments we could show that engagement of the costimulatory molecule 4-1BB enhances NF-κB and AP-1 activity, whereas coinhibition via PD-1 or BTLA strongly reduced the activation of NF-κB and NFAT. Engagement of BTLA significantly inhibited AP-1, whereas PD-1 had little effect on the activation of this transcription factor. Our triple parameter reporter T cell line is an excellent tool to assess the effect of costimulatory and coinhibitory receptors on NF-κB, NFAT and AP-1 activity and has a wide range of applications beyond the evaluation of costimulatory pathways.
Topics: CD2 Antigens; CD28 Antigens; CD3 Complex; Genes, Reporter; Humans; Jurkat Cells; Luminescent Proteins; Lymphocyte Activation; NF-kappa B; NFATC Transcription Factors; Signal Transduction; Transcription Factor AP-1; Red Fluorescent Protein
PubMed: 26780292
DOI: 10.1016/j.jim.2016.01.007 -
Cell Apr 2015Pioneer transcription factors (TFs) access silent chromatin and initiate cell-fate changes, using diverse types of DNA binding domains (DBDs). FoxA, the paradigm pioneer...
Pioneer transcription factors (TFs) access silent chromatin and initiate cell-fate changes, using diverse types of DNA binding domains (DBDs). FoxA, the paradigm pioneer TF, has a winged helix DBD that resembles linker histone and thereby binds its target sites on nucleosomes and in compacted chromatin. Herein, we compare the nucleosome and chromatin targeting activities of Oct4 (POU DBD), Sox2 (HMG box DBD), Klf4 (zinc finger DBD), and c-Myc (bHLH DBD), which together reprogram somatic cells to pluripotency. Purified Oct4, Sox2, and Klf4 proteins can bind nucleosomes in vitro, and in vivo they preferentially target silent sites enriched for nucleosomes. Pioneer activity relates simply to the ability of a given DBD to target partial motifs displayed on the nucleosome surface. Such partial motif recognition can occur by coordinate binding between factors. Our findings provide insight into how pioneer factors can target naive chromatin sites.
Topics: Amino Acid Sequence; Cell Dedifferentiation; Cellular Reprogramming; DNA; Fibroblasts; Humans; Induced Pluripotent Stem Cells; Kruppel-Like Factor 4; Models, Molecular; Nucleosomes; Nucleotide Motifs; Octamer Transcription Factor-3; Protein Structure, Tertiary; Sequence Alignment; Transcription Factors
PubMed: 25892221
DOI: 10.1016/j.cell.2015.03.017 -
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 -
British Journal of Haematology May 2015The IKZF1 gene at 7p12.2 codes for IKAROS (also termed IKZF1), an essential transcription factor in haematopoiesis involved primarily in lymphoid differentiation. Its... (Review)
Review
The IKZF1 gene at 7p12.2 codes for IKAROS (also termed IKZF1), an essential transcription factor in haematopoiesis involved primarily in lymphoid differentiation. Its importance is underlined by the fact that deregulation of IKAROS results in leukaemia in both mice and men. During recent years, constitutional as well as acquired genetic changes of IKZF1 have been associated with human disease. For example, certain germline single nucleotide polymorphisms in IKZF1 have been shown to increase the risk of some disorders and abnormal expression and somatic rearrangements, mutations and deletions of IKZF1 (ΔIKZF1) have been detected in a wide variety of human malignancies. Of immediate clinical importance is the fact that ΔIKZF1 occurs in 15% of paediatric B-cell precursor acute lymphoblastic leukaemia (BCP ALL) and that the presence of ΔIKZF1 is associated with an increased risk of relapse and a poor outcome; in some studies such deletions have been shown to be an independent risk factor also when minimal residual disease data are taken into account. However, cooperative genetic changes, such as ERG deletions and CRLF2 rearrangements, may modify the prognostic impact of ΔIKZF1, for better or worse. This review summarizes our current knowledge of IKZF1 abnormalities in human disease, with an emphasis on BCP ALL.
Topics: Animals; Gene Deletion; Humans; Ikaros Transcription Factor; Mice; Oncogene Proteins; Polymorphism, Single Nucleotide; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Cytokine; Trans-Activators; Transcription Factors; Transcriptional Regulator ERG
PubMed: 25753742
DOI: 10.1111/bjh.13342