Showing papers on "Transcription factor published in 2020"
TL;DR: The PI3K–AKT signalling network is discussed and its control of cancer cell metabolism through both direct and indirect regulation of nutrient transport and metabolic enzymes, thereby connecting oncogenic signalling and metabolic reprogramming to support cancer cell survival and proliferation.
Abstract: The altered metabolic programme of cancer cells facilitates their cell-autonomous proliferation and survival. In normal cells, signal transduction pathways control core cellular functions, including metabolism, to couple the signals from exogenous growth factors, cytokines or hormones to adaptive changes in cell physiology. The ubiquitous, growth factor-regulated phosphoinositide 3-kinase (PI3K)-AKT signalling network has diverse downstream effects on cellular metabolism, through either direct regulation of nutrient transporters and metabolic enzymes or the control of transcription factors that regulate the expression of key components of metabolic pathways. Aberrant activation of this signalling network is one of the most frequent events in human cancer and serves to disconnect the control of cell growth, survival and metabolism from exogenous growth stimuli. Here we discuss our current understanding of the molecular events controlling cellular metabolism downstream of PI3K and AKT and of how these events couple two major hallmarks of cancer: growth factor independence through oncogenic signalling and metabolic reprogramming to support cell survival and proliferation.
860 citations
TL;DR: During progression and metastasis, tumor cells adapt to oxidative stress by increasing NADPH in various ways, including activation of AMPK, the PPP, and reductive glutamine and folate metabolism.
852 citations
TL;DR: The integration of the KEAP1-NRF2 system into multiple cellular signaling and metabolic pathways places NRF2 activation as a critical regulatory node in many disease phenotypes and suggests that the pharmaceutical modulation of NRF 2’s cytoprotective activity will be beneficial for human health in a broad range of noncommunicable diseases.
Abstract: The KEAP1-NRF2 pathway is the principal protective response to oxidative and electrophilic stresses. Under homeostatic conditions, KEAP1 forms part of an E3 ubiquitin ligase, which tightly regulates the activity of the transcription factor NRF2 by targeting it for ubiquitination and proteasome-dependent degradation. In response to stress, an intricate molecular mechanism facilitated by sensor cysteines within KEAP1 allows NRF2 to escape ubiquitination, accumulate within the cell, and translocate to the nucleus, where it can promote its antioxidant transcription program. Recent advances have revealed that KEAP1 contains multiple stress sensors and inactivation modalities, which together allow diverse cellular inputs, from oxidative stress and cellular metabolites to dysregulated autophagy, to regulate NRF2 activity. This integration of the KEAP1-NRF2 system into multiple cellular signaling and metabolic pathways places NRF2 activation as a critical regulatory node in many disease phenotypes and suggests that the pharmaceutical modulation of NRF2's cytoprotective activity will be beneficial for human health in a broad range of noncommunicable diseases.
448 citations
TL;DR: The complex regulatory network of NRF2 activity and its roles in metabolic reprogramming, unfolded protein response, proteostasis, autophagy, mitochondrial biogenesis, inflammation, and immunity are summarized.
Abstract: Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that regulates the cellular defense against toxic and oxidative insults through the expression of genes involved in oxidative stress response and drug detoxification. NRF2 activation renders cells resistant to chemical carcinogens and inflammatory challenges. In addition to antioxidant responses, NRF2 is involved in many other cellular processes, including metabolism and inflammation, and its functions are beyond the originally envisioned. NRF2 activity is tightly regulated through a complex transcriptional and post-translational network that enables it to orchestrate the cell's response and adaptation to various pathological stressors for the homeostasis maintenance. Elevated or decreased NRF2 activity by pharmacological and genetic manipulations of NRF2 activation is associated with many metabolism- or inflammation-related diseases. Emerging evidence shows that NRF2 lies at the center of a complex regulatory network and establishes NRF2 as a truly pleiotropic transcription factor. Here we summarize the complex regulatory network of NRF2 activity and its roles in metabolic reprogramming, unfolded protein response, proteostasis, autophagy, mitochondrial biogenesis, inflammation, and immunity.
416 citations
TL;DR: This study uncovers previously obscured finer-scale genome organization, establishing functional links between chromatin folding and gene regulation by using high-resolution Micro-C to probe links between 3D genome organization and transcriptional regulation in mouse stem cells.
312 citations
TL;DR: This study establishes INs-seq as a broadly applicable technology for elucidating integrated transcriptional and intra-cellular maps and identifies the molecular signature of myeloid suppressive cells in tumors.
248 citations
TL;DR: It is shown that somatosensory neurogenesis gives rise to neurons in a transcriptionally unspecialized state, characterized by co-expression of transcription factors that become restricted to select subtypes as development proceeds, and this support a model in which cues that emanate from intermediate and final target fields promote neuronal diversification in part by transitioning cells from a transcriptally un specialized state to transcriptionally distinct subtypes by modulating the selection of subtype-restricted transcription factors.
Abstract: More than twelve morphologically and physiologically distinct subtypes of primary somatosensory neuron report salient features of our internal and external environments1–4. It is unclear how specialized gene expression programs emerge during development to endow these subtypes with their unique properties. To assess the developmental progression of transcriptional maturation of each subtype of principal somatosensory neuron, we generated a transcriptomic atlas of cells traversing the primary somatosensory neuron lineage in mice. Here we show that somatosensory neurogenesis gives rise to neurons in a transcriptionally unspecialized state, characterized by co-expression of transcription factors that become restricted to select subtypes as development proceeds. Single-cell transcriptomic analyses of sensory neurons from mutant mice lacking transcription factors suggest that these broad-to-restricted transcription factors coordinate subtype-specific gene expression programs in subtypes in which their expression is maintained. We also show that neuronal targets are involved in this process; disruption of the prototypic target-derived neurotrophic factor NGF leads to aberrant subtype-restricted patterns of transcription factor expression. Our findings support a model in which cues that emanate from intermediate and final target fields promote neuronal diversification in part by transitioning cells from a transcriptionally unspecialized state to transcriptionally distinct subtypes by modulating the selection of subtype-restricted transcription factors. Neuronal targets mediate the emergence of somatosensory neuron subtypes by altering the expression of neuronal transcription factors.
241 citations
TL;DR: A recurring theme of EGR1 transcriptional activity in connective tissues, regulating genes related to the extracellular matrix is revealed.
Abstract: Although the transcription factor EGR1 is known as NGF1-A, TIS8, Krox24, zif/268, and ZENK, it still has many fewer names than biological functions. A broad range of signals induce Egr1 gene expression via numerous regulatory elements identified in the Egr1 promoter. EGR1 is also the target of multiple post-translational modifications, which modulate EGR1 transcriptional activity. Despite the myriad regulators of Egr1 transcription and translation, and the numerous biological functions identified for EGR1, the literature reveals a recurring theme of EGR1 transcriptional activity in connective tissues, regulating genes related to the extracellular matrix. Egr1 is expressed in different connective tissues, such as tendon (a dense connective tissue), cartilage and bone (supportive connective tissues), and adipose tissue (a loose connective tissue). Egr1 is involved in the development, homeostasis, and healing processes of these tissues, mainly via the regulation of extracellular matrix. In addition, Egr1 is often involved in the abnormal production of extracellular matrix in fibrotic conditions, and Egr1 deletion is seen as a target for therapeutic strategies to fight fibrotic conditions. This generic EGR1 function in matrix regulation has little-explored implications but is potentially important for tendon repair.
221 citations
TL;DR: RREB1 provides a molecular link between RAS and TGF-β pathways for coordinated induction of developmental and fibrogenic EMTs, and increases the understanding of the regulation of epithelial plasticity and its pathophysiological consequences in development, fibrosis and cancer.
Abstract: Epithelial-to-mesenchymal transitions (EMTs) are phenotypic plasticity processes that confer migratory and invasive properties to epithelial cells during development, wound-healing, fibrosis and cancer1–4. EMTs are driven by SNAIL, ZEB and TWIST transcription factors5,6 together with microRNAs that balance this regulatory network7,8. Transforming growth factor β (TGF-β) is a potent inducer of developmental and fibrogenic EMTs4,9,10. Aberrant TGF-β signalling and EMT are implicated in the pathogenesis of renal fibrosis, alcoholic liver disease, non-alcoholic steatohepatitis, pulmonary fibrosis and cancer4,11. TGF-β depends on RAS and mitogen-activated protein kinase (MAPK) pathway inputs for the induction of EMTs12–19. Here we show how these signals coordinately trigger EMTs and integrate them with broader pathophysiological processes. We identify RAS-responsive element binding protein 1 (RREB1), a RAS transcriptional effector20,21, as a key partner of TGF-β-activated SMAD transcription factors in EMT. MAPK-activated RREB1 recruits TGF-β-activated SMAD factors to SNAIL. Context-dependent chromatin accessibility dictates the ability of RREB1 and SMAD to activate additional genes that determine the nature of the resulting EMT. In carcinoma cells, TGF-β–SMAD and RREB1 directly drive expression of SNAIL and fibrogenic factors stimulating myofibroblasts, promoting intratumoral fibrosis and supporting tumour growth. In mouse epiblast progenitors, Nodal–SMAD and RREB1 combine to induce expression of SNAIL and mesendoderm-differentiation genes that drive gastrulation. Thus, RREB1 provides a molecular link between RAS and TGF-β pathways for coordinated induction of developmental and fibrogenic EMTs. These insights increase our understanding of the regulation of epithelial plasticity and its pathophysiological consequences in development, fibrosis and cancer. RAS and TGF-β pathways regulate distinct modes of epithelial-to-mesenchymal transition via RAS-responsive element binding protein 1.
212 citations
TL;DR: Although this canonical pathway is the predominant signaling cascade, alternative pathways also affect ethylene responses, and this review summarizes the current understanding of ethylene signaling, including these alternative pathways, and discusses how Ethylene signaling has been manipulated for agricultural and horticultural applications.
210 citations
TL;DR: The current understanding of the mechanisms by which pioneer factors initiate gene network changes and will ultimately contribute to the ability to control cell fates at will are focused on.
Abstract: Pioneer transcription factors have the intrinsic biochemical ability to scan partial DNA sequence motifs that are exposed on the surface of a nucleosome and thus access silent genes that are inaccessible to other transcription factors. Pioneer factors subsequently enable other transcription factors, nucleosome remodeling complexes, and histone modifiers to engage chromatin, thereby initiating the formation of an activating or repressive regulatory sequence. Thus, pioneer factors endow the competence for fate changes in embryonic development, are essential for cellular reprogramming, and rewire gene networks in cancer cells. Recent studies with reconstituted nucleosomes in vitro and chromatin binding in vivo reveal that pioneer factors can directly perturb nucleosome structure and chromatin accessibility in different ways. This review focuses on our current understanding of the mechanisms by which pioneer factors initiate gene network changes and will ultimately contribute to our ability to control cell fates at will.
TL;DR: A high-density DNase I cleavage map from 243 human cell and tissue types provides a genome-wide, nucleotide-resolution map of human transcription factor footprints, and shows that the enrichment of genetic variants associated with diseases or phenotypic traits in regulatory regions is almost entirely attributable to variants within footprints.
Abstract: Combinatorial binding of transcription factors to regulatory DNA underpins gene regulation in all organisms. Genetic variation in regulatory regions has been connected with diseases and diverse phenotypic traits1, but it remains challenging to distinguish variants that affect regulatory function2. Genomic DNase I footprinting enables the quantitative, nucleotide-resolution delineation of sites of transcription factor occupancy within native chromatin3–6. However, only a small fraction of such sites have been precisely resolved on the human genome sequence6. Here, to enable comprehensive mapping of transcription factor footprints, we produced high-density DNase I cleavage maps from 243 human cell and tissue types and states and integrated these data to delineate about 4.5 million compact genomic elements that encode transcription factor occupancy at nucleotide resolution. We map the fine-scale structure within about 1.6 million DNase I-hypersensitive sites and show that the overwhelming majority are populated by well-spaced sites of single transcription factor–DNA interaction. Cell-context-dependent cis-regulation is chiefly executed by wholesale modulation of accessibility at regulatory DNA rather than by differential transcription factor occupancy within accessible elements. We also show that the enrichment of genetic variants associated with diseases or phenotypic traits in regulatory regions1,7 is almost entirely attributable to variants within footprints, and that functional variants that affect transcription factor occupancy are nearly evenly partitioned between loss- and gain-of-function alleles. Unexpectedly, we find increased density of human genetic variation within transcription factor footprints, revealing an unappreciated driver of cis-regulatory evolution. Our results provide a framework for both global and nucleotide-precision analyses of gene regulatory mechanisms and functional genetic variation. A high-density DNase I cleavage map from 243 human cell and tissue types provides a genome-wide, nucleotide-resolution map of human transcription factor footprints.
TL;DR: It is demonstrated that TAZ forms nuclear condensates through liquid–liquid phase separation to compartmentalize its DNA-binding cofactor TEAD4, coactivators BRD4 and MED1, and the transcription elongation factor CDK9 for transcription.
Abstract: TAZ promotes growth, development and tumorigenesis by regulating the expression of target genes. However, the manner in which TAZ orchestrates the transcriptional responses is poorly defined. Here we demonstrate that TAZ forms nuclear condensates through liquid-liquid phase separation to compartmentalize its DNA-binding cofactor TEAD4, coactivators BRD4 and MED1, and the transcription elongation factor CDK9 for transcription. TAZ forms phase-separated droplets in vitro and liquid-like nuclear condensates in vivo, and this ability is negatively regulated by Hippo signalling through LATS-mediated phosphorylation and is mediated by the coiled-coil (CC) domain. Deletion of the TAZ CC domain or substitution with the YAP CC domain prevents the phase separation of TAZ and its ability to induce the expression of TAZ-specific target genes. Thus, we identify a mechanism of transcriptional activation by TAZ and demonstrate that pathway-specific transcription factors also engage the phase-separation mechanism for efficient and specific transcriptional activation.
TL;DR: Gene expression levels in yeast are predicted using a massive dataset on promoters with random sequences, showing that massive-throughput assays of fully random DNA can provide the big data necessary to develop complex, predictive models of gene regulation.
Abstract: How transcription factors (TFs) interpret cis-regulatory DNA sequence to control gene expression remains unclear, largely because past studies using native and engineered sequences had insufficient scale. Here, we measure the expression output of >100 million synthetic yeast promoter sequences that are fully random. These sequences yield diverse, reproducible expression levels that can be explained by their chance inclusion of functional TF binding sites. We use machine learning to build interpretable models of transcriptional regulation that predict ~94% of the expression driven from independent test promoters and ~89% of the expression driven from native yeast promoter fragments. These models allow us to characterize each TF's specificity, activity and interactions with chromatin. TF activity depends on binding-site strand, position, DNA helical face and chromatin context. Notably, expression level is influenced by weak regulatory interactions, which confound designed-sequence studies. Our analyses show that massive-throughput assays of fully random DNA can provide the big data necessary to develop complex, predictive models of gene regulation.
TL;DR: The emerging role of transcription factors and epigenetic remodelling in macrophages in the context of atherosclerosis and inflammation, and a comprehensive overview of epigenetic enzymes and transcription factors that are involved in Macrophage activation are discussed.
Abstract: Monocytes and macrophages provide defence against pathogens and danger signals. These cells respond to stimulation in a fast and stimulus-specific manner by utilizing complex cascaded activation by lineage-determining and signal-dependent transcription factors. The complexity of the functional response is determined by interactions between triggered transcription factors and depends on the microenvironment and interdependent signalling cascades. Dysregulation of macrophage phenotypes is a major driver of various diseases such as atherosclerosis, rheumatoid arthritis and type 2 diabetes mellitus. Furthermore, exposure of monocytes, which are macrophage precursor cells, to certain stimuli can lead to a hypo-inflammatory tolerized phenotype or a hyper-inflammatory trained phenotype in a macrophage. In atherosclerosis, macrophages and monocytes are exposed to inflammatory cytokines, oxidized lipids, cholesterol crystals and other factors. All these stimuli induce not only a specific transcriptional response but also interact extensively, leading to transcriptional and epigenetic heterogeneity of macrophages in atherosclerotic plaques. Targeting the epigenetic landscape of plaque macrophages can be a powerful therapeutic tool to modulate pro-atherogenic phenotypes and reduce the rate of plaque formation. In this Review, we discuss the emerging role of transcription factors and epigenetic remodelling in macrophages in the context of atherosclerosis and inflammation, and provide a comprehensive overview of epigenetic enzymes and transcription factors that are involved in macrophage activation.
TL;DR: It is found that TAF15 has a unique charge distribution among the FET family members that enhances its interactions with the C-terminal domain of RNA polymerase II, suggesting that positive feedback between interacting transcriptional components drives localized phase separation to amplify gene expression.
Abstract: Membraneless organelles or condensates form through liquid–liquid phase separation1–4, which is thought to underlie gene transcription through condensation of the large-scale nucleolus5–7 or in smaller assemblies known as transcriptional condensates8–11. Transcriptional condensates have been hypothesized to phase separate at particular genomic loci and locally promote the biomolecular interactions underlying gene expression. However, there have been few quantitative biophysical tests of this model in living cells, and phase separation has not yet been directly linked with dynamic transcriptional outputs12,13. Here, we apply an optogenetic approach to show that FET-family transcriptional regulators exhibit a strong tendency to phase separate within living cells, a process that can drive localized RNA transcription. We find that TAF15 has a unique charge distribution among the FET family members that enhances its interactions with the C-terminal domain of RNA polymerase II. Nascent C-terminal domain clusters at primed genomic loci lower the energetic barrier for nucleation of TAF15 condensates, which in turn further recruit RNA polymerase II to drive transcriptional output. These results suggest that positive feedback between interacting transcriptional components drives localized phase separation to amplify gene expression. Wei et al. show that clusters of unphosphorylated RNA polymerase II seed the nucleation of phase-separated condensates of TAF15, which further recruit RNA polymerase II to amplify transcriptional activation.
TL;DR: Genomic-wide analysis indicated that AP2/ERF transcription factors were highly conserved during plant evolution and will provide important bases for plant regulatory mechanisms and molecular breeding.
Abstract: In the whole life process, many factors including external and internal factors affect plant growth and development. The morphogenesis, growth, and development of plants are controlled by genetic elements and are influenced by environmental stress. Transcription factors contain one or more specific DNA-binding domains, which are essential in the whole life cycle of higher plants. The AP2/ERF (APETALA2/ethylene-responsive element binding factors) transcription factors are a large group of factors that are mainly found in plants. The transcription factors of this family serve as important regulators in many biological and physiological processes, such as plant morphogenesis, responsive mechanisms to various stresses, hormone signal transduction, and metabolite regulation. In this review, we summarized the advances in identification, classification, function, regulatory mechanisms, and the evolution of AP2/ERF transcription factors in plants. AP2/ERF family factors are mainly classified into four major subfamilies: DREB (Dehydration Responsive Element-Binding), ERF (Ethylene-Responsive-Element-Binding protein), AP2 (APETALA2) and RAV (Related to ABI3/VP), and Soloists (few unclassified factors). The review summarized the reports about multiple regulatory functions of AP2/ERF transcription factors in plants. In addition to growth regulation and stress responses, the regulatory functions of AP2/ERF in plant metabolite biosynthesis have been described. We also discussed the roles of AP2/ERF transcription factors in different phytohormone-mediated signaling pathways in plants. Genomic-wide analysis indicated that AP2/ERF transcription factors were highly conserved during plant evolution. Some public databases containing the information of AP2/ERF have been introduced. The studies of AP2/ERF factors will provide important bases for plant regulatory mechanisms and molecular breeding.
TL;DR: Many of the molecular targets of strigolactones—plant hormones involved in development and in interactions with symbiotic and parasitic organisms—are uncovered, revealing how striglactones function and an intriguing role for self-regulation of a downstream transcription factor.
Abstract: Plant hormones known as strigolactones control plant development and interactions between host plants and symbiotic fungi or parasitic weeds1–4. In Arabidopsis thaliana and rice, the proteins DWARF14 (D14), MORE AXILLARY GROWTH 2 (MAX2), SUPPRESSOR OF MAX2-LIKE 6, 7 and 8 (SMXL6, SMXL7 and SMXL8) and their orthologues form a complex upon strigolactone perception and play a central part in strigolactone signalling5–10. However, whether and how strigolactones activate downstream transcription remains largely unknown. Here we use a synthetic strigolactone to identify 401 strigolactone-responsive genes in Arabidopsis, and show that these plant hormones regulate shoot branching, leaf shape and anthocyanin accumulation mainly through transcriptional activation of the BRANCHED 1, TCP DOMAIN PROTEIN 1 and PRODUCTION OF ANTHOCYANIN PIGMENT 1 genes. We find that SMXL6 targets 729 genes in the Arabidopsis genome and represses the transcription of SMXL6, SMXL7 and SMXL8 by binding directly to their promoters, showing that SMXL6 serves as an autoregulated transcription factor to maintain the homeostasis of strigolactone signalling. These findings reveal an unanticipated mechanism through which a transcriptional repressor of hormone signalling can directly recognize DNA and regulate transcription in higher plants. Many of the molecular targets of strigolactones—plant hormones involved in development and in interactions with symbiotic and parasitic organisms—are uncovered, revealing how strigolactones function and an intriguing role for self-regulation of a downstream transcription factor.
TL;DR: A Myb-like transcription factor (BFD1) necessary for differentiation in cell culture and in mice is identified and represents a counterpoint to the ApiAP2 factors that dominate the current view of parasite gene regulation.
TL;DR: It is argued that the mechanism by which MYC proteins regulate the transcription machinery is likely to promote tumorigenesis independently of global or relative changes in the expression of their target genes.
Abstract: Oncoproteins of the MYC family are major drivers of human tumorigenesis. Since a large body of evidence indicates that MYC proteins are transcription factors, studying their function has focused on the biology of their target genes. Detailed studies of MYC-dependent changes in RNA levels have provided contrasting models of the oncogenic activity of MYC proteins through either enhancing or repressing the expression of specific target genes, or as global amplifiers of transcription. In this Review, we first summarize the biochemistry of MYC proteins and what is known (or is unclear) about the MYC target genes. We then discuss recent progress in defining the interactomes of MYC and MYCN and how this information affects central concepts of MYC biology, focusing on mechanisms by which MYC proteins modulate transcription. MYC proteins promote transcription termination upon stalling of RNA polymerase II, and we propose that this mechanism enhances the stress resilience of basal transcription. Furthermore, MYC proteins coordinate transcription elongation with DNA replication and cell cycle progression. Finally, we argue that the mechanism by which MYC proteins regulate the transcription machinery is likely to promote tumorigenesis independently of global or relative changes in the expression of their target genes. The MYC oncoproteins are transcription factors, but the molecular mechanism of their oncogenic activity is unclear. MYC proteins promote transcription termination in stress conditions, which is proposed to increase cellular resilience to stress and to promote tumorigenesis independently of changes in the expression of their target genes.
TL;DR: The concepts that emerge in different cellular systems allow the design of NF-kB function in humans to allow the development for rare diseases associated withNF-kB, but would also be used as a source of useful information to eliminate widespread consequences such as cancer or inflammatory/immune diseases.
Abstract: The nuclear factor kappa B (NF-kB) family of transcription factors plays an essential role as stressors in the cellular environment, and controls the expression of important regulatory genes such as immunity, inflammation, death, and cell proliferation. NF-kB protein is located in the cytoplasm, and can be activated by various cellular stimuli. There are two pathways for NF-kB activation, as the canonical and non-canonical pathways, which require complex molecular interactions with adapter proteins and phosphorylation and ubiquitinase enzymes. Accordingly, this increases NF-kB translocation in the nucleus and regulates gene expression. In this study, the concepts that emerge in different cellular systems allow the design of NF-kB function in humans. This would not only allow the development for rare diseases associated with NF-kB, but would also be used as a source of useful information to eliminate widespread consequences such as cancer or inflammatory/immune diseases.
TL;DR: The transcriptional landscape of mouse tumor-infiltrating natural killer cells is defined by using single-cell RNA sequencing and inhibition of HIF-1α unleashes NK cell anti-tumor activity and could be exploited for cancer therapy.
TL;DR: C comprehending mode of actions of miRNAs and their possible roles during SARS-CoV-2 infections could create new opportunities for the development and improvement of new therapeutics.
Abstract: MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression found in more than 200 diverse organisms. Although it is still not fully established if RNA viruses could generate miRNAs, there are examples of miRNA like sequences from RNA viruses with regulatory functions. In the case of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), there are several mechanisms that would make miRNAs impact the virus, like interfering with viral replication, translation and even modulating the host expression. In this study, we performed a machine learning based miRNA prediction analysis for the SARS-CoV-2 genome to identify miRNA-like hairpins and searched for potential miRNA-based interactions between the viral miRNAs and human genes and human miRNAs and viral genes. Overall, 950 hairpin structured sequences were extracted from the virus genome and based on the prediction results, 29 of them could be precursor miRNAs. Targeting analysis showed that 30 viral mature miRNA-like sequences could target 1,367 different human genes. PANTHER gene function analysis results indicated that viral derived miRNA candidates could target various human genes involved in crucial cellular processes including transcription, metabolism, defense system and several signaling pathways such as Wnt and EGFR signalings. Protein class-based grouping of targeted human genes showed that host transcription might be one of the main targets of the virus since 96 genes involved in transcriptional processes were potential targets of predicted viral miRNAs. For instance, basal transcription machinery elements including several components of human mediator complex (MED1, MED9, MED12L, MED19), basal transcription factors such as TAF4, TAF5, TAF7L and site-specific transcription factors such as STAT1 were found to be targeted. In addition, many known human miRNAs appeared to be able to target viral genes involved in viral life cycle such as S, M, N, E proteins and ORF1ab, ORF3a, ORF8, ORF7a and ORF10. Considering the fact that miRNA-based therapies have been paid attention, based on the findings of this study, comprehending mode of actions of miRNAs and their possible roles during SARS-CoV-2 infections could create new opportunities for the development and improvement of new therapeutics.
TL;DR: Cryo-electron microscopy structures of the DNA-binding domains of the pioneer transcription factor SOX2 and its close homologue SOX11 elucidate the role of these factors in initiating chromatin opening and nucleosome remodelling and subsequent transcription.
Abstract: ‘Pioneer’ transcription factors are required for stem-cell pluripotency, cell differentiation and cell reprogramming1,2. Pioneer factors can bind nucleosomal DNA to enable gene expression from regions of the genome with closed chromatin. SOX2 is a prominent pioneer factor that is essential for pluripotency and self-renewal of embryonic stem cells3. Here we report cryo-electron microscopy structures of the DNA-binding domains of SOX2 and its close homologue SOX11 bound to nucleosomes. The structures show that SOX factors can bind and locally distort DNA at superhelical location 2. The factors also facilitate detachment of terminal nucleosomal DNA from the histone octamer, which increases DNA accessibility. SOX-factor binding to the nucleosome can also lead to a repositioning of the N-terminal tail of histone H4 that includes residue lysine 16. We speculate that this repositioning is incompatible with higher-order nucleosome stacking, which involves contacts of the H4 tail with a neighbouring nucleosome. Our results indicate that pioneer transcription factors can use binding energy to initiate chromatin opening, and thereby facilitate nucleosome remodelling and subsequent transcription. Cryo-electron microscopy structures of the DNA-binding domains of the pioneer transcription factor SOX2 and its close homologue SOX11 elucidate the role of these factors in initiating chromatin opening and nucleosome remodelling.
TL;DR: How NF-κB, a master transcription factor of inflammation and immunity, is emerging as a key positive regulator of PD-L1 expression in cancer is discussed, suggesting that PD- L1 is part of the tissue remodeling program in tumors.
Abstract: Immune checkpoints are inhibitory receptor/ligand pairs regulating immunity that are exploited as key targets of anti-cancer therapy. Although the PD-1/PD-L1 pair is one of the most studied immune checkpoints, several aspects of its biology remain to be clarified. It has been established that PD-1 is an inhibitory receptor up-regulated by activated T, B, and NK lymphocytes and that its ligand PD-L1 mediates a negative feedback of lymphocyte activation, contributing to the restoration of the steady state condition after acute immune responses. This loop might become detrimental in the presence of either a chronic infection or a growing tumor. PD-L1 expression in tumors is currently used as a biomarker to orient therapeutic decisions; nevertheless, our knowledge about the regulation of PD-L1 expression is limited. The present review discusses how NF-κB, a master transcription factor of inflammation and immunity, is emerging as a key positive regulator of PD-L1 expression in cancer. NF-κB directly induces PD-L1 gene transcription by binding to its promoter, and it can also regulate PD-L1 post-transcriptionally through indirect pathways. These processes, which under conditions of cellular stress and acute inflammation drive tissue homeostasis and promote tissue healing, are largely dysregulated in tumors. Up-regulation of PD-L1 in cancer cells is controlled via NF-κB downstream of several signals, including oncogene- and stress-induced pathways, inflammatory cytokines, and chemotherapeutic drugs. Notably, a shared signaling pathway in epithelial cancers induces both PD-L1 expression and epithelial-mesenchymal transition, suggesting that PD-L1 is part of the tissue remodeling program. Furthermore, PD-L1 expression by tumor infiltrating myeloid cells can contribute to the immune suppressive features of the tumor environment. A better understanding of the interplay between NF-κB signaling and PD-L1 expression is highly relevant to cancer biology and therapy.
TL;DR: It is reported that mammalian mitochondrial DNA (mtDNA) is enriched for 6mA, which is at least 1,300-fold higher than that in gDNA under normal growth conditions, corresponding to approximately four 6mA modifications on each mtDNA molecule.
TL;DR: Data show that DNAme shapes the topography of hematopoietic differentiation, and support a model in which genome-wide methylation changes are transduced to differentiation skews through biases in CpG enrichment of the transcription factor binding motifs.
Abstract: Mutations in genes involved in DNA methylation (DNAme; for example, TET2 and DNMT3A) are frequently observed in hematological malignancies1–3 and clonal hematopoiesis4,5. Applying single-cell sequencing to murine hematopoietic stem and progenitor cells, we observed that these mutations disrupt hematopoietic differentiation, causing opposite shifts in the frequencies of erythroid versus myelomonocytic progenitors following Tet2 or Dnmt3a loss. Notably, these shifts trace back to transcriptional priming skews in uncommitted hematopoietic stem cells. To reconcile genome-wide DNAme changes with specific erythroid versus myelomonocytic skews, we provide evidence in support of differential sensitivity of transcription factors due to biases in CpG enrichment in their binding motif. Single-cell transcriptomes with targeted genotyping showed similar skews in transcriptional priming of DNMT3A-mutated human clonal hematopoiesis bone marrow progenitors. These data show that DNAme shapes the topography of hematopoietic differentiation, and support a model in which genome-wide methylation changes are transduced to differentiation skews through biases in CpG enrichment of the transcription factor binding motif. Single-cell analysis of mouse hematopoietic stem cells shows that mutations in DNA methylation genes change the frequencies of erythroid versus myelomonocytic progenitors, owing to differential CpG enrichment in transcription factor binding motifs.
TL;DR: This review attempts to elaborate on role of small molecule inhibitors of HDACs on neuronal differentiation and throws light on the potential ofHDAC inhibitors as therapeutic agents for treatment of neurodegenerative diseases.
Abstract: Histone deacetylases (HADC) are the enzymes that remove acetyl group from lysine residue of histones and non-histone proteins and regulate the process of transcription by binding to transcription factors and regulating fundamental cellular process such as cellular proliferation, differentiation and development. In neurodegenerative diseases, the histone acetylation homeostasis is greatly impaired, shifting towards a state of hypoacetylation. The histone hyperacetylation produced by direct inhibition of HDACs leads to neuroprotective actions. This review attempts to elaborate on role of small molecule inhibitors of HDACs on neuronal differentiation and throws light on the potential of HDAC inhibitors as therapeutic agents for treatment of neurodegenerative diseases. The role of HDACs in neuronal cellular and disease models and their modulation with HDAC inhibitors are also discussed. Significance of these HDAC inhibitors has been reviewed on the process of neuronal differentiation, neurite outgrowth and neuroprotection regarding their potential therapeutic application for treatment of neurodegenerative diseases.
TL;DR: It is found that the transcript encoding the bHLH transcription factor PIF7 undergoes a direct increase in translation in response to warmer temperature, suggesting that this is a conserved mechanism enabling plants to respond and adapt rapidly to high temperatures.
Abstract: Temperature is a major environmental cue affecting plant growth and development. Plants often experience higher temperatures in the context of a 24 h day–night cycle, with temperatures peaking in the middle of the day. Here, we find that the transcript encoding the bHLH transcription factor PIF7 undergoes a direct increase in translation in response to warmer temperature. Diurnal expression of PIF7 transcript gates this response, allowing PIF7 protein to quickly accumulate in response to warm daytime temperature. Enhanced PIF7 protein levels directly activate the thermomorphogenesis pathway by inducing the transcription of key genes such as the auxin biosynthetic gene YUCCA8, and are necessary for thermomorphogenesis to occur under warm cycling daytime temperatures. The temperature-dependent translational enhancement of PIF7 messenger RNA is mediated by the formation of an RNA hairpin within its 5′ untranslated region, which adopts an alternative conformation at higher temperature, leading to increased protein synthesis. We identified similar hairpin sequences that control translation in additional transcripts including WRKY22 and the key heat shock regulator HSFA2, suggesting that this is a conserved mechanism enabling plants to respond and adapt rapidly to high temperatures. Temperature-dependent translational enhancement of PIF7 promotes gene expression for thermomorphogenesis in Arabidopsis during warm daytime. This enhanced translation is mediated by an RNA hairpin which shifts conformation at higher temperatures.
TL;DR: An understanding of how signalling networks integrate with the FOXO transcription factors to modulate their developmental, metabolic and tumour-suppressive functions in normal tissues and in cancer will offer a new perspective on tumorigenesis and metastasis, and open up therapeutic opportunities for malignant diseases.
Abstract: Forkhead box O (FOXO) transcription factors regulate diverse biological processes, affecting development, metabolism, stem cell maintenance and longevity. They have also been increasingly recognised as tumour suppressors through their ability to regulate genes essential for cell proliferation, cell death, senescence, angiogenesis, cell migration and metastasis. Mechanistically, FOXO proteins serve as key connection points to allow diverse proliferative, nutrient and stress signals to converge and integrate with distinct gene networks to control cell fate, metabolism and cancer development. In consequence, deregulation of FOXO expression and function can promote genetic disorders, metabolic diseases, deregulated ageing and cancer. Metastasis is the process by which cancer cells spread from the primary tumour often via the bloodstream or the lymphatic system and is the major cause of cancer death. The regulation and deregulation of FOXO transcription factors occur predominantly at the post-transcriptional and post-translational levels mediated by regulatory non-coding RNAs, their interactions with other protein partners and co-factors and a combination of post-translational modifications (PTMs), including phosphorylation, acetylation, methylation and ubiquitination. This review discusses the role and regulation of FOXO proteins in tumour initiation and progression, with a particular emphasis on cancer metastasis. An understanding of how signalling networks integrate with the FOXO transcription factors to modulate their developmental, metabolic and tumour-suppressive functions in normal tissues and in cancer will offer a new perspective on tumorigenesis and metastasis, and open up therapeutic opportunities for malignant diseases.