Showing papers on "Transcription factor published in 2014"
TL;DR: The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues, and the convergence of signalling pathways is essential for EMT.
Abstract: The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial-mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix-loop-helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT.
6,036 citations
Alistair R. R. Forrest, Hideya Kawaji, Michael Rehli1, J Kenneth Baillie2 +277 more•Institutions (63)
TL;DR: For example, the authors mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body.
Abstract: Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body We find that few genes are truly 'housekeeping', whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved Promoter-based expression analysis reveals key transcription factors defining cell states and links them to binding-site motifs The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research
1,715 citations
TL;DR: Well known for its role in tumour cell proliferation, survival, invasion and immunosuppression, JAK–STAT3 signalling also promotes cancer through inflammation, obesity, stem cells and the pre-metastatic niche.
Abstract: The Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) proteins, particularly STAT3, are among the most promising new targets for cancer therapy. In addition to interleukin-6 (IL-6) and its family members, multiple pathways, including G-protein-coupled receptors (GPCRs), Toll-like receptors (TLRs) and microRNAs were recently identified to regulate JAK-STAT signalling in cancer. Well known for its role in tumour cell proliferation, survival, invasion and immunosuppression, JAK-STAT3 signalling also promotes cancer through inflammation, obesity, stem cells and the pre-metastatic niche. In addition to its established role as a transcription factor in cancer, STAT3 regulates mitochondrion functions, as well as gene expression through epigenetic mechanisms. Newly identified regulators and functions of JAK-STAT3 in tumours are important targets for potential therapeutic strategies in the treatment of cancer.
1,572 citations
University of Toronto1, Cincinnati Children's Hospital Medical Center2, Pontifical Catholic University of Chile3, Kettering University4, Icahn School of Medicine at Mount Sinai5, University of Paris6, Salk Institute for Biological Studies7, Baylor College of Medicine8, University of Cincinnati9, University of Massachusetts Medical School10
TL;DR: DNA sequence preferences for >1,000 TFs encompassing 54 different DBD classes from 131 diverse eukaryotes are determined, finding that closely related DBDs almost always have very similar DNA sequence preferences, enabling inference of motifs for ∼34% of the ∼170,000 known or predicted eUKaryotic TFs.
1,419 citations
TL;DR: Using quantitative proteomics, it is found that lenalidomide causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKzF3, by the CRBN-CRL4 ubiquitin ligase, which are essential transcription factors in multiple myeloma.
Abstract: Lenalidomide is a drug with clinical efficacy in multiple myeloma and other B cell neoplasms, but its mechanism of action is unknown. Using quantitative proteomics, we found that lenalidomide causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. IKZF1 and IKZF3 are essential transcription factors in multiple myeloma. A single amino acid substitution of IKZF3 conferred resistance to lenalidomide-induced degradation and rescued lenalidomide-induced inhibition of cell growth. Similarly, we found that lenalidomide-induced interleukin-2 production in T cells is due to depletion of IKZF1 and IKZF3. These findings reveal a previously unknown mechanism of action for a therapeutic agent: alteration of the activity of an E3 ubiquitin ligase, leading to selective degradation of specific targets.
1,254 citations
TL;DR: This review discusses how intracellular pathways and extracellular signals that regulate gene expression to induce EMT crosstalk and respond to signals from the microenvironment to regulate the expression and function of EMT-inducing transcription factors in development, physiology, and disease.
Abstract: The epithelial-mesenchymal transition (EMT) is an essential mechanism in embryonic development and tissue repair. EMT also contributes to the progression of disease, including organ fibrosis and cancer. EMT, as well as a similar transition occurring in vascular endothelial cells called endothelial-mesenchymal transition (EndMT), results from the induction of transcription factors that alter gene expression to promote loss of cell-cell adhesion, leading to a shift in cytoskeletal dynamics and a change from epithelial morphology and physiology to the mesenchymal phenotype. Transcription program switching in EMT is induced by signaling pathways mediated by transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP), Wnt-β-catenin, Notch, Hedgehog, and receptor tyrosine kinases. These pathways are activated by various dynamic stimuli from the local microenvironment, including growth factors and cytokines, hypoxia, and contact with the surrounding extracellular matrix (ECM). We discuss how these pathways crosstalk and respond to signals from the microenvironment to regulate the expression and function of EMT-inducing transcription factors in development, physiology, and disease. Understanding these mechanisms will enable the therapeutic control of EMT to promote tissue regeneration, treat fibrosis, and prevent cancer metastasis.
1,194 citations
TL;DR: It is found that distinct tissue environments drive divergent programs of gene expression by differentially activating a common enhancer repertoire and by inducing the expression of divergent secondary transcription factors that collaborate with PU.1 to establish tissue-specific enhancers.
971 citations
TL;DR: A lncRNA expressed exclusively in human dendritic cells (DC), called lnc-DC, is identified that is required for optimal DC differentiation from human monocytes and that regulates DC activation of T cells.
Abstract: Long noncoding RNAs (lncRNAs) play important roles in diverse biological processes; however, few have been identified that regulate immune cell differentiation and function. Here, we identified lnc-DC, which was exclusively expressed in human conventional dendritic cells (DCs). Knockdown of lnc-DC impaired DC differentiation from human monocytes in vitro and from mouse bone marrow cells in vivo and reduced capacity of DCs to stimulate T cell activation. lnc-DC mediated these effects by activating the transcription factor STAT3 (signal transducer and activator of transcription 3). lnc-DC bound directly to STAT3 in the cytoplasm, which promoted STAT3 phosphorylation on tyrosine-705 by preventing STAT3 binding to and dephosphorylation by SHP1. Our work identifies a lncRNA that regulates DC differentiation and also broadens the known mechanisms of lncRNA action.
871 citations
TL;DR: Because of its vital role in various biologic activities, components of the NF-κB pathway need to be carefully selected and evaluated to design targeted therapies.
Abstract: NF-κB comprises a family of five transcription factors that form distinct protein complexes, which bind to consensus DNA sequences at promoter regions of responsive genes regulating cellular processes. The past three decades have witnessed remarkable progress in understanding the NF-κB signaling pathway in physiologic and pathologic conditions. The role of NF-κB in human cancer initiation, development, metastasis, and resistance to treatment has drawn particular attention. A significant number of human cancers have constitutive NF-κB activity due to the inflammatory microenvironment and various oncogenic mutations. NF-κB activity not only promotes tumor cells' proliferation, suppresses apoptosis, and attracts angiogenesis, but it also induces epithelial-mesenchymal transition, which facilitates distant metastasis. In certain circumstances, NF-κB activation may also remodel local metabolism and anergize the immune system to favor tumor growth. Suppression of NF-κB in myeloid cells or tumor cells usually leads to tumor regression, which makes the NF-κB pathway a promising therapeutic target. However, because of its vital role in various biologic activities, components of the NF-κB pathway need to be carefully selected and evaluated to design targeted therapies.
840 citations
TL;DR: How oxygen sensing in the immune microenvironment shapes immunological response is discussed and how HIF and the hypoxia pathway control innate and adaptive immunity is examined.
822 citations
TL;DR: This work shows that disruption of Xrn1 activity preferentially affects both the synthesis and decay of a distinct subpopulation of mRNAs, and proposes to name the most affected genes “Xrn1 synthegradon.”
Abstract: The 5’ to 3’ exoribonuclease Xrn1 is a large protein involved in cytoplasmatic mRNA degradation as a critical component of the major decaysome. Its deletion in the yeast Saccharomyces cerevisiae is not lethal, but it has multiple physiological effects. In a previous study, our group showed that deletion of all tested components of the yeast major decaysome, including XRN1, results in a decrease in the synthetic rate and an increase in half-life of most mRNAs in a compensatory manner. Furthermore, the same study showed that the all tested decaysome components are also nuclear proteins that bind to the 5’ region of a number of genes. In the present work, we show that disruption of Xrn1 activity preferentially affects both the synthesis and decay of a distinct subpopulation of mRNAs. The most affected mRNAs are the transcripts of the highly transcribed genes, mainly those encoding ribosome biogenesis and translation factors. Previously, we proposed that synthegradases play a key role in regulating both mRNA synthesis and degradation. Evidently, Xrn1 functions as a synthegradase, whose selectivity might help coordinating the expression of the protein synthetic machinery. We propose to name the most affected genes “Xrn1 synthegradon”.
TL;DR: A high-sensitivity indexing-first chromatin immunoprecipitation approach to profile the dynamics of four chromatin modifications across 16 stages of hematopoietic differentiation and reveals that lineage commitment involves de novo establishment of 17,035 lineage-specific enhancers.
Abstract: Chromatin modifications are crucial for development, yet little is known about their dynamics during differentiation. Hematopoiesis provides a well-defined model to study chromatin state dynamics; however, technical limitations impede profiling of homogeneous differentiation intermediates. We developed a high-sensitivity indexing-first chromatin immunoprecipitation approach to profile the dynamics of four chromatin modifications across 16 stages of hematopoietic differentiation. We identify 48,415 enhancer regions and characterize their dynamics. We find that lineage commitment involves de novo establishment of 17,035 lineage-specific enhancers. These enhancer repertoire expansions foreshadow transcriptional programs in differentiated cells. Combining our enhancer catalog with gene expression profiles, we elucidate the transcription factor network controlling chromatin dynamics and lineage specification in hematopoiesis. Together, our results provide a comprehensive model of chromatin dynamics during development.
TL;DR: This review highlights transcriptional regulation of gene expression governed by two key transcription factors: AREB/ABFs and DREB2A operating respectively in ABA-dependent and A BA-independent signaling pathways.
TL;DR: The multitude of H2O2 targets and mechanisms provides an opportunity for highly specific effects on gene regulation that depend on the cell type and on signals received from the cellular microenvironment.
Abstract: The regulatory mechanisms by which hydrogen peroxide (H2O2) modulates the activity of transcription factors in bacteria (OxyR and PerR), lower eukaryotes (Yap1, Maf1, Hsf1 and Msn2/4) and mammalian cells (AP-1, NRF2, CREB, HSF1, HIF-1, TP53, NF-κB, NOTCH, SP1 and SCREB-1) are reviewed The complexity of regulatory networks increases throughout the phylogenetic tree, reaching a high level of complexity in mammalians Multiple H2O2 sensors and pathways are triggered converging in the regulation of transcription factors at several levels: (1) synthesis of the transcription factor by upregulating transcription or increasing both mRNA stability and translation; (ii) stability of the transcription factor by decreasing its association with the ubiquitin E3 ligase complex or by inhibiting this complex; (iii) cytoplasm–nuclear traffic by exposing/masking nuclear localization signals, or by releasing the transcription factor from partners or from membrane anchors; and (iv) DNA binding and nuclear transactivation by modulating transcription factor affinity towards DNA, co-activators or repressors, and by targeting specific regions of chromatin to activate individual genes We also discuss how H2O2 biological specificity results from diverse thiol protein sensors, with different reactivity of their sulfhydryl groups towards H2O2, being activated by different concentrations and times of exposure to H2O2 The specific regulation of local H2O2 concentrations is also crucial and results from H2O2 localized production and removal controlled by signals Finally, we formulate equations to extract from typical experiments quantitative data concerning H2O2 reactivity with sensor molecules Rate constants of 140 M−1 s−1 and ≥13 × 103 M−1 s−1 were estimated, respectively, for the reaction of H2O2 with KEAP1 and with an unknown target that mediates NRF2 protein synthesis In conclusion, the multitude of H2O2 targets and mechanisms provides an opportunity for highly specific effects on gene regulation that depend on the cell type and on signals received from the cellular microenvironment
TL;DR: The discovery and characterization of a covalent CDK7 inhibitor, THZ1, is presented, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity forCDK7.
Abstract: Tumour oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state, but direct pharmacological inhibition of transcription factors has so far proven difficult. However, the transcriptional machinery contains various enzymatic cofactors that can be targeted for the development of new therapeutic candidates, including cyclin-dependent kinases (CDKs). Here we present the discovery and characterization of a covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell-line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukaemia (T-ALL), have exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL cells shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and the key role of RUNX1 in the core transcriptional regulatory circuitry of these tumour cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumour types that are dependent on transcription for maintenance of the oncogenic state.
TL;DR: In this paper, the authors identify a genetic mechanism responsible for the generation of oncogenic super-enhancers in malignant cells in acute lymphoblastic leukemia (T-ALL) cases.
Abstract: In certain human cancers, the expression of critical oncogenes is driven from large regulatory elements, called super-enhancers, that recruit much of the cell’s transcriptional apparatus and are defined by extensive acetylation of histone H3 lysine 27 (H3K27ac). In a subset of T-cell acute lymphoblastic leukemia (T-ALL) cases, we found that heterozygous somatic mutations are acquired that introduce binding motifs for the MYB transcription factor in a precise noncoding site, which creates a super-enhancer upstream of the TAL1 oncogene. MYB binds to this new site and recruits its H3K27 acetylase–binding partner CBP, as well as core components of a major leukemogenic transcriptional complex that contains RUNX1, GATA-3, and TAL1 itself. Additionally, most endogenous super-enhancers found in T-ALL cells are occupied by MYB and CBP, which suggests a general role for MYB in super-enhancer initiation. Thus, this study identifies a genetic mechanism responsible for the generation of oncogenic super-enhancers in malignant cells.
TL;DR: It is found that acquired resistance to Kras suppression in a Kras-driven murine lung cancer model also involved increased YAP1 signaling, which implicate transcriptional regulation of EMT by Yap1 as a significant component of oncogenic RAS signaling.
TL;DR: The role of long noncoding RNA (lncRNA) in adult heart is unknown; also unclear is how lncRNA modulates nucleosome remodelling as discussed by the authors. But they identify a cluster of LncRNA transcripts from myosin heavy chain 7 (Myh7) loci and demonstrate a new lnc RNA-chromatin mechanism for heart failure.
Abstract: The role of long noncoding RNA (lncRNA) in adult hearts is unknown; also unclear is how lncRNA modulates nucleosome remodelling. An estimated 70% of mouse genes undergo antisense transcription, including myosin heavy chain 7 (Myh7), which encodes molecular motor proteins for heart contraction. Here we identify a cluster of lncRNA transcripts from Myh7 loci and demonstrate a new lncRNA-chromatin mechanism for heart failure. In mice, these transcripts, which we named myosin heavy-chain-associated RNA transcripts (Myheart, or Mhrt), are cardiac-specific and abundant in adult hearts. Pathological stress activates the Brg1-Hdac-Parp chromatin repressor complex to inhibit Mhrt transcription in the heart. Such stress-induced Mhrt repression is essential for cardiomyopathy to develop: restoring Mhrt to the pre-stress level protects the heart from hypertrophy and failure. Mhrt antagonizes the function of Brg1, a chromatin-remodelling factor that is activated by stress to trigger aberrant gene expression and cardiac myopathy. Mhrt prevents Brg1 from recognizing its genomic DNA targets, thus inhibiting chromatin targeting and gene regulation by Brg1. It does so by binding to the helicase domain of Brg1, a domain that is crucial for tethering Brg1 to chromatinized DNA targets. Brg1 helicase has dual nucleic-acid-binding specificities: it is capable of binding lncRNA (Mhrt) and chromatinized--but not naked--DNA. This dual-binding feature of helicase enables a competitive inhibition mechanism by which Mhrt sequesters Brg1 from its genomic DNA targets to prevent chromatin remodelling. A Mhrt-Brg1 feedback circuit is thus crucial for heart function. Human MHRT also originates from MYH7 loci and is repressed in various types of myopathic hearts, suggesting a conserved lncRNA mechanism in human cardiomyopathy. Our studies identify a cardioprotective lncRNA, define a new targeting mechanism for ATP-dependent chromatin-remodelling factors, and establish a new paradigm for lncRNA-chromatin interaction.
TL;DR: Analysis of comprehensive mapping of transcription start sites in human lymphoblastoid B cell and chronic myelogenous leukemic ENCODE Tier 1 cell lines identifies a common architecture of initiation, including tightly spaced (110 bp apart) divergent initiation, similar frequencies of core promoter sequence elements, highly positioned flanking nucleosomes and two modes of transcription factor binding.
Abstract: Despite the conventional distinction between them, promoters and enhancers share many features in mammals, including divergent transcription and similar modes of transcription factor binding. Here we examine the architecture of transcription initiation through comprehensive mapping of transcription start sites (TSSs) in human lymphoblastoid B cell (GM12878) and chronic myelogenous leukemic (K562) ENCODE Tier 1 cell lines. Using a nuclear run-on protocol called GRO-cap, which captures TSSs for both stable and unstable transcripts, we conduct detailed comparisons of thousands of promoters and enhancers in human cells. These analyses identify a common architecture of initiation, including tightly spaced (110 bp apart) divergent initiation, similar frequencies of core promoter sequence elements, highly positioned flanking nucleosomes and two modes of transcription factor binding. Post-initiation transcript stability provides a more fundamental distinction between promoters and enhancers than patterns of histone modification and association of transcription factors or co-activators. These results support a unified model of transcription initiation at promoters and enhancers.
TL;DR: By characterizing the target sequence specificity of 63 plant TFs representing 25 families, using protein-binding microarrays, the data support the correlation between cis-regulatory elements in vivo and the sequence determined in vitro and provides a framework to explore regulatory networks in plants.
Abstract: Transcription factors (TFs) regulate gene expression through binding to cis-regulatory specific sequences in the promoters of their target genes. In contrast to the genetic code, the transcriptional regulatory code is far from being deciphered and is determined by sequence specificity of TFs, combinatorial cooperation between TFs and chromatin competence. Here we addressed one of these determinants by characterizing the target sequence specificity of 63 plant TFs representing 25 families, using protein-binding microarrays. Remarkably, almost half of these TFs recognized secondary motifs, which in some cases were completely unrelated to the primary element. Analyses of coregulated genes and transcriptomic data from TFs mutants showed the functional significance of over 80% of all identified sequences and of at least one target sequence per TF. Moreover, combining the target sequence information with coexpression analysis we could predict the function of a TF as activator or repressor through a particular DNA sequence. Our data support the correlation between cis-regulatory elements and the sequence determined in vitro using the protein-binding microarray and provides a framework to explore regulatory networks in plants.
TL;DR: The evidence for critical roles ofSTAT3 in oncogenesis is presented and the potential for development of novel cancer therapies based on mechanistic understanding of STAT3 signaling cascade is discussed.
TL;DR: How the various HIF polypeptides, their posttranslational modifications, binding partners and transcriptional cofactors affect RNA polymerase II activity to drive context-dependent transcriptional programs during hypoxia is discussed.
Abstract: The cellular response to oxygen deprivation is governed largely by a family of transcription factors known as Hypoxia Inducible Factors (HIFs). This review focuses on the molecular mechanisms by which HIFs regulate the transcriptional apparatus to enable the cellular and organismal response to hypoxia. We discuss here how the various HIF polypeptides, their posttranslational modifications, binding partners and transcriptional cofactors affect RNA polymerase II activity to drive context-dependent transcriptional programs during hypoxia.
TL;DR: Understanding the means by which pioneer factors can engage closed chromatin and how heterochromatin can prevent such binding promises to advance the ability to reprogram cell fates at will is the topic of this review.
Abstract: A subset of eukaryotic transcription factors possesses the remarkable ability to reprogram one type of cell into another. The transcription factors that reprogram cell fate are invariably those that are crucial for the initial cell programming in embryonic development. To elicit cell programming or reprogramming, transcription factors must be able to engage genes that are developmentally silenced and inappropriate for expression in the original cell. Developmentally silenced genes are typically embedded in "closed" chromatin that is covered by nucleosomes and not hypersensitive to nuclease probes such as DNase I. Biochemical and genomic studies have shown that transcription factors with the highest reprogramming activity often have the special ability to engage their target sites on nucleosomal DNA, thus behaving as "pioneer factors" to initiate events in closed chromatin. Other reprogramming factors appear dependent on pioneer factors for engaging nucleosomes and closed chromatin. However, certain genomic domains in which nucleosomes are occluded by higher-order chromatin structures, such as in heterochromatin, are resistant to pioneer factor binding. Understanding the means by which pioneer factors can engage closed chromatin and how heterochromatin can prevent such binding promises to advance our ability to reprogram cell fates at will and is the topic of this review.
TL;DR: A chemical genetic approach reveals a requirement for BET bromodomains in communicating enhancer remodeling to RNA Polymerase II and orchestrating the transition to the inflammatory cell state, demonstrated in activated endothelium and macrophages.
TL;DR: The identification of transcription factor E3 (TFE3) as another regulator of lysosomal homeostasis that induced expression of genes encoding proteins involved in autophagy and lYSosomal biogenesis in ARPE-19 cells in response to starvation and lysOSomal stress is reported.
Abstract: The discovery of a gene network regulating lysosomal biogenesis and its transcriptional regulator transcription factor EB (TFEB) revealed that cells monitor lysosomal function and respond to degradation requirements and environmental cues. We report the identification of transcription factor E3 (TFE3) as another regulator of lysosomal homeostasis that induced expression of genes encoding proteins involved in autophagy and lysosomal biogenesis in ARPE-19 cells in response to starvation and lysosomal stress. We found that in nutrient-replete cells, TFE3 was recruited to lysosomes through interaction with active Rag guanosine triphosphatases (GTPases) and exhibited mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1)-dependent phosphorylation. Phosphorylated TFE3 was retained in the cytosol through its interaction with the cytosolic chaperone 14-3-3. After starvation, TFE3 rapidly translocated to the nucleus and bound to the CLEAR elements present in the promoter region of many lysosomal genes, thereby inducing lysosomal biogenesis. Depletion of endogenous TFE3 entirely abolished the response of ARPE-19 cells to starvation, suggesting that TFE3 plays a critical role in nutrient sensing and regulation of energy metabolism. Furthermore, overexpression of TFE3 triggered lysosomal exocytosis and resulted in efficient cellular clearance in a cellular model of a lysosomal storage disorder, Pompe disease, thus identifying TFE3 as a potential therapeutic target for the treatment of lysosomal disorders.
TL;DR: In this article, a molecular circuit that integrates all major growth-regulating signals, including auxin, brassinosteroid, gibberellin, light, and temperature, is presented.
Abstract: As the major mechanism of plant growth and morphogenesis, cell elongation is controlled by many hormonal and environmental signals. How these signals are coordinated at the molecular level to ensure coherent cellular responses remains unclear. In this study, we illustrate a molecular circuit that integrates all major growth-regulating signals, including auxin, brassinosteroid, gibberellin, light, and temperature. Analyses of genome-wide targets, genetic and biochemical interactions demonstrate that the auxin-response factor ARF6, the light/temperature-regulated transcription factor PIF4, and the brassinosteroid-signaling transcription factor BZR1, interact with each other and cooperatively regulate large numbers of common target genes, but their DNA-binding activities are blocked by the gibberellin-inactivated repressor RGA. In addition, a tripartite HLH/bHLH module feedback regulates PIFs and additional bHLH factors that interact with ARF6, and thereby modulates auxin sensitivity according to developmental and environmental cues. Our results demonstrate a central growth-regulation circuit that integrates hormonal, environmental, and developmental controls of cell elongation in Arabidopsis hypocotyl.
TL;DR: The regulation of RUNX2 by factors commonly used during osteogenic studies will be discussed and the complexity of its regulation and its interactions within the osteoblast differentiation pathway are often overlooked.
Abstract: Runt-related transcription factor 2 (RUNX2) is a transcription factor closely associated with the osteoblast phenotype. While frequently referred to, the complexity of its regulation and its interactions within the osteoblast differentiation pathway are often overlooked. This review aims to summarise the knowledge of its regulation at the transcriptional, translational and post-translational level. In addition, the regulation of RUNX2 by factors commonly used during osteogenic studies will be discussed.
01 Jun 2014
TL;DR: In this article, a covalent cyclin-dependent kinase inhibitor, THZ1, was proposed to target a remote cysteine residue located outside of the canonical kinase domain.
Abstract: Tumour oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state, but direct pharmacological inhibition of transcription factors has so far proven difficult. However, the transcriptional machinery contains various enzymatic cofactors that can be targeted for the development of new therapeutic candidates, including cyclin-dependent kinases (CDKs). Here we present the discovery and characterization of a covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell-line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukaemia (T-ALL), have exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL cells shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and the key role of RUNX1 in the core transcriptional regulatory circuitry of these tumour cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumour types that are dependent on transcription for maintenance of the oncogenic state.
TL;DR: It is demonstrated that transition between these two pluripotent states is associated with widespread Oct4 relocalization, mirrored by global rearrangement of enhancer chromatin landscapes, and suggested that the capacity of transcription factors such as Otx2 and Oct4 to pioneer new enhancer sites is highly context dependent.
TL;DR: Emerging evidence for a pivotal role of FOXO factors in promoting the expression of genes involved in autophagy and the ubiquitin-proteasome system--two cell clearance processes that are essential for maintaining organelle and protein homeostasis (proteostasis) is discussed.