Modulation Of Transcription Factors Research Articles

Constitutive expression of bZIP19 with the Zn sensor motif deleted in Arabidopsis leads to Zn-specific accumulation and no visible developmental penalty

Abstract Aims The transcription factors bZIP19 and bZIP23 function as central regulators of the Zn deficiency response, and also as sensors of intracellular Zn concentration through their protein Zn-Sensor Motif (ZSM). While under Zn deficiency the target genes of bZIP19/23 are transcriptionally activated, under Zn sufficiency the binding of Zn2+ ions to the ZSM halts gene expression. Mutations, including deletions, in the ZSM affect the activity of bZIP19/23 and leads to a Zn-insensitive and constitutive activation of target gene expression. Here we investigated the effects of such deregulation of the Zn deficiency response on plant growth and Zn accumulation, and evaluate whether this deregulation influences Cd accumulation. Methods We analysed Arabidopsis lines constitutively expressing bZIP19 with the ZSM deleted and measured developmental traits and ionomics in soil-grown plants, comparing control and Cd-spiked soils. Results Results indicated that deletion of the ZSM, and the consequent deregulation of the Zn deficiency response, does not cause visible penalties in plant growth, development or reproduction. Compared with the wild-type, bZIP19-ZSM deletion increased Zn accumulation in leaves and seeds, and such an increase was mostly limited to Zn. In seeds, the increased Zn content appears distributed evenly throughout the embryo. Exposure of bZIP19-ZSM deletion to a low-level Cd contamination did not cause enhanced Cd accumulation, which is important given that Cd uptake is a concern in crop Zn biofortification. Finally, we verified that the bZIP19-ZSM deletion represents a gain-of-function dominant mutation. Conclusion Together, results support that modulation of F-bZIP transcription factor’s activity may be a promising avenue for Zn biofortification in crops.

Transcriptional modules and hormonal metabolic pathways reveal the critical role of TgHB12-like in the regulation of flower opening and petal senescence in Tulipa gesneriana

Tulips (Tulipa gesneriana) are one of the most widely cultivated bulbous plants with substantial ornamental value. However, the lack of well-documented reference genomes has limited the research progress and molecular breeding of tulips. In the present study, a full-length transcriptome of a commercial tulip cultivar was obtained using single-molecule long-read sequencing (PacBio Iso-Seq). In total, 244,357 full-length transcripts were identified, which had an average length of 2,044 bp and an N50 value of 3,861; 67,350 of these were annotated to databases. An inaugural integrated analysis of the transcriptome and phytohormone profiles during flower opening and petal senescence was performed using Illumina RNA-seq, coupled with Mfuzz (an R pakage, http://mfuzz.sysbiolab.eu) and weighted gene coexpression network analysis (WGCNA). A total of 16 gene coexpression and six transcription factor (TF) modules were constructed. Additionally, 26 hormone analogs were comprehensively profiled. Finally, a prominently novel gene, Tulipa gesneriana Homeobox12-like (TgHB12-like), which encodes an homeodomain–leucine zipper (HD-zip) TF, was identified as a pivotal regulator of petal senescence. Overall, this work facilitates the identification of hormones and TFs in plants related to flower opening and senescence in tulips. It also provides an important and valuable genetic basis for further research in them.

UCHL1-dependent control of hypoxia-inducible factor transcriptional activity during liver fibrosis.

Liver fibrosis is the excessive accumulation of extracellular matrix proteins that occurs in most types of chronic liver disease. At the cellular level, liver fibrosis is associated with the activation of hepatic stellate cells (HSCs) which transdifferentiate into a myofibroblast-like phenotype that is contractile, proliferative and profibrogenic. HSC transdifferentiation induces genome-wide changes in gene expression that enable the cell to adopt its profibrogenic functions. We have previously identified that the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) is highly induced following HSC activation; however, the cellular targets of its deubiquitinating activity are poorly defined. Here, we describe a role for UCHL1 in regulating the levels and activity of hypoxia-inducible factor 1 (HIF1), an oxygen-sensitive transcription factor, during HSC activation and liver fibrosis. HIF1 is elevated during HSC activation and promotes the expression of profibrotic mediator HIF target genes. Increased HIF1α expression correlated with induction of UCHL1 mRNA and protein with HSC activation. Genetic deletion or chemical inhibition of UCHL1 impaired HIF activity through reduction of HIF1α levels. Furthermore, our mechanistic studies have shown that UCHL1 elevates HIF activity through specific cleavage of degradative ubiquitin chains, elevates levels of pro-fibrotic gene expression and increases proliferation rates. As we also show that UCHL1 inhibition blunts fibrogenesis in a pre-clinical 3D human liver slice model of fibrosis, these results demonstrate how small molecule inhibitors of DUBs can exert therapeutic effects through modulation of HIF transcription factors in liver disease. Furthermore, inhibition of HIF activity using UCHL1 inhibitors may represent a therapeutic opportunity with other HIF-related pathologies.

Selective activation of cellular stress response pathways by fumaric acid esters.

The cellular response to oxidants or xenobiotics comprises two key pathways, resulting in modulation of NRF2 and FOXO transcription factors, respectively. Both mount a cytoprotective response, and their activation relies on crucial protein thiol moieties. Using fumaric acid esters (FAEs), known thiol-reactive compounds, we tested for activation of NRF2 and FOXO pathways in cultured human hepatoma cells by dimethyl/diethyl as well as monomethyl/monoethyl fumarate. Whereas only the diesters caused acute glutathione depletion and activation of the stress kinase p38MAPK, all four FAEs stimulated NRF2 stabilization and upregulation of NRF2 target genes. However, no significant FAE-induced activation of FOXO-dependent target gene expression was observed. Therefore, while both NRF2 and FOXO pathways are responsive to oxidants and xenobiotics, FAEs selectively activate NRF2 signaling.

Macrophage Polarization and Functions in Pathogenesis of Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD), the major leading cause of mortality worldwide, is a progressive and irreversible respiratory condition characterized by peripheral airway and lung parenchymal inflammation, accompanied by fibrosis, emphysema, and airflow limitation, and has multiple etiologies, including genetic variance, air pollution, and repetitive exposure to harmful substances. However, the precise mechanisms underlying the pathogenesis of COPD have not been identified. Recent multiomics-based evidence suggests that the plasticity of alveolar macrophages contributes to the onset and progression of COPD through the coordinated modulation of numerous transcription factors. Therefore, this review focuses on understanding the mechanisms and functions of macrophage polarization that regulate lung homeostasis in COPD. These findings may provide a better insight into the distinct role of macrophages in COPD pathogenesis and perspective for developing novel therapeutic strategies targeting macrophage polarization.

Context-dependent role of sirtuin 2 in inflammation.

Sirtuin 2 is a member of the sirtuin family nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases, known for its regulatory role in different processes, including inflammation. In this context, sirtuin 2 has been involved in the modulation of key inflammatory signaling pathways and transcription factors by deacetylating specific targets, such as nuclear factor κB and nucleotide-binding oligomerization domain-leucine-rich-repeat and pyrin domain-containing protein 3 (NLRP3). However, whether sirtuin 2-mediated pathways induce a pro- or an anti-inflammatory response remains controversial. Sirtuin 2 has been implicated in promoting inflammation in conditions such as asthma and neurodegenerative diseases, suggesting that its inhibition in these conditions could be a potential therapeutic strategy. Conversely, arthritis and type 2 diabetes mellitus studies suggest that sirtuin 2 is essential at the peripheral level and, thus, its inhibition in these pathologies would not be recommended. Overall, the precise role of sirtuin 2 in inflammation appears to be context-dependent, and further investigation is needed to determine the specific molecular mechanisms and downstream targets through which sirtuin 2 influences inflammatory processes in various tissues and pathological conditions. The present review explores the involvement of sirtuin 2 in the inflammation associated with different pathologies to elucidate whether its pharmacological modulation could serve as an effective strategy for treating this prevalent symptom across various diseases.

Effects of Cranberry Extract (Vaccinium macrocarpon) Supplementation on Lipid Peroxidation and Inflammation in Patients with Chronic Kidney Disease (Stages 3-4): A Randomized Controlled Trial.

Growing evidence suggests that bioactive compounds in berry fruits may mitigate inflammation in patients with chronic kidney disease (CKD). To evaluate cranberry (Vaccinium macrocarpon) supplementation effects on modulation of transcription factors involved in inflammation and oxidative stress in nondialysis (stages 3 and 4) patients with CKD. Design/Participants. A randomized, double-blind, placebo-controlled study was performed with 30 patients to receive capsules containing cranberry extract (1000 mg/day) or placebo (1000 mg/day of corn starch) for two months. Measurements. The mRNA expression of nuclear factor-erythroid 2-related factor-2 (Nrf2) and nuclear factor-kB (NF-kB) was evaluated in peripheral blood mononuclear cells (PBMCs) by quantitative real-time polymerase chain reaction. Thiobarbituric acid reactive substances (TBARS) were measured in the plasma to assess oxidative stress. Interleukin-6 (IL-6) plasma levels were assessed by enzyme-linked immunosorbent assay and C-reactive protein (CRP) by immunoturbidimetric method. Twenty-five patients completed the study: 12 in the cranberry group (56.7 ± 7.5 years and body mass index (BMI) of 29.6 ± 5.5 kg/m2) and 13 in the placebo group (58.8 ± 5.1 years and BMI 29.8 ± 5.4 kg/m2). There were no differences in NF-kB or Nrf2 mRNA expressions (p = 0.99 and p = 0.89) or TBARS, CRP, and IL-6 plasma levels after cranberry supplementation. The cranberry extract administration (1000 mg/day) did not affect Nrf2 and NF-kB mRNA expression, oxidative stress, or inflammatory markers levels in nondialysis CKD patients. This trial is registered with NCT04377919.

The role of CBL-CIPK signaling in plant responses to biotic and abiotic stresses.

Plants have a variety of regulatory mechanisms to perceive, transduce, and respond to biotic and abiotic stress. One such mechanism is the calcium-sensing CBL-CIPK system responsible for the sensing of specific stressors, such as drought or pathogens. CBLs perceive and bind Calcium (Ca2+) in response to stress and then interact with CIPKs to form an activated complex. This leads to the phosphorylation of downstream targets, including transporters and ion channels, and modulates transcription factor levels and the consequent levels of stress-associated genes. This review describes the mechanisms underlying the response of the CBL-CIPK pathway to biotic and abiotic stresses, including regulating ion transport channels, coordinating plant hormone signal transduction, and pathways related to ROS signaling. Investigation of the function of the CBL-CIPK pathway is important for understanding plant stress tolerance and provides a promising avenue for molecular breeding.

Unravelling the biostimulant activity of a protein hydrolysate in lettuce plants under optimal and low N availability: a multi-omics approach.

The application of protein hydrolysates (PH) biostimulants is considered a promising approach to promote crop growth and resilience against abiotic stresses. Nevertheless, PHs bioactivity depends on both the raw material used for their preparation and the molecular fraction applied. The present research aimed at investigating the molecular mechanisms triggered by applying a PH and its fractions on plants subjected to nitrogen limitations. To this objective, an integrated transcriptomic-metabolomic approach was used to assess lettuce plants grown under different nitrogen levels and treated with either the commercial PH Vegamin® or its molecular fractions PH1(>10 kDa), PH2 (1-10 kDa) and PH3 (<1 kDa). Regardless of nitrogen provision, biostimulant application enhanced lettuce biomass, likely through a hormone-like activity. This was confirmed by the modulation of genes involved in auxin and cytokinin synthesis, mirrored by an increase in the metabolic levels of these hormones. Consistently, PH and PH3 upregulated genes involved in cell wall growth and plasticity. Furthermore, the accumulation of specific metabolites suggested the activation of a multifaceted antioxidant machinery. Notwithstanding, the modulation of stress-response transcription factors and genes involved in detoxification processes was observed. The coordinated action of these molecular entities might underpin the increased resilience of lettuce plants against nitrogen-limiting conditions. In conclusion, integrating omics techniques allowed the elucidation of mechanistic aspects underlying PH bioactivity in crops. Most importantly, the comparison of PH with its fraction PH3 showed that, except for a few peculiarities, the effects induced were equivalent, suggesting that the highest bioactivity was ascribable to the lightest molecular fraction.

Stem-Cell-Driven Chondrogenesis: Perspectives on Amnion-Derived Cells.

Regenerative medicine harnesses stem cells' capacity to restore damaged tissues and organs. In vitro methods employing specific bioactive molecules, such as growth factors, bio-inductive scaffolds, 3D cultures, co-cultures, and mechanical stimuli, steer stem cells toward the desired differentiation pathways, mimicking their natural development. Chondrogenesis presents a challenge for regenerative medicine. This intricate process involves precise modulation of chondro-related transcription factors and pathways, critical for generating cartilage. Cartilage damage disrupts this process, impeding proper tissue healing due to its unique mechanical and anatomical characteristics. Consequently, the resultant tissue often forms fibrocartilage, which lacks adequate mechanical properties, posing a significant hurdle for effective regeneration. This review comprehensively explores studies showcasing the potential of amniotic mesenchymal stem cells (AMSCs) and amniotic epithelial cells (AECs) in chondrogenic differentiation. These cells exhibit innate characteristics that position them as promising candidates for regenerative medicine. Their capacity to differentiate toward chondrocytes offers a pathway for developing effective regenerative protocols. Understanding and leveraging the innate properties of AMSCs and AECs hold promise in addressing the challenges associated with cartilage repair, potentially offering superior outcomes in tissue regeneration.

Antagonistic control of rice immunity against distinct pathogens by the two transcription modules via salicylic acid and jasmonic acid pathways

Although the antagonistic effects of host resistance against biotrophic and necrotrophic pathogens have been documented in various plants, the underlying mechanisms are unknown. Here, we investigated the antagonistic resistance mediated by the transcription factor ETHYLENE-INSENSITIVE3-LIKE 3 (OsEIL3) in rice. The Oseil3 mutant confers enhanced resistance to the necrotroph Rhizoctonia solani but greater susceptibility to the hemibiotroph Magnaporthe oryzae and biotroph Xanthomonas oryzae pv. oryzae. OsEIL3 directly activates OsERF040 transcription while repressing OsWRKY28 transcription. The infection of R.solani and M.oryzae or Xoo influences the extent of binding of OsEIL3 to OsWRKY28 and OsERF040 promoters, resulting in the repression or activation of both salicylic acid (SA)- and jasmonic acid (JA)-dependent pathways and enhanced susceptibility or resistance, respectively. These results demonstrate that the distinct effects of plant immunity to different pathogen types are determined by two transcription factor modules that control transcriptional reprogramming and the SA and JA pathways.

Multifaceted physiological and therapeutical impact of curcumin on hormone-related endocrine dysfunctions: A comprehensive review.

Over the past five decades, Curcumin (Cur), derived from turmeric (Curcuma longa), has gained considerable attention for its potential therapeutic applications. Synthesizing insights from clinical trials conducted over the last 25 years, this review delves into diseases where Cur has demonstrated promise, offering a nuanced understanding of its pharmacokinetics, safety, and effectiveness. Focusing on specific examples, the impact of Cur on various human diseases is explored. Endocrine glands and associated signaling pathways are highlighted, elucidating how Cur influences cellular signaling. The article underscores molecular mechanisms such as hormone level alteration, receptor interaction, cytokine and adipokine expression inhibition, antioxidant enzyme activity, and modulation of transcription factors. Cur showcases diverse protective mechanisms against inflammation and oxidative damage by suppressing antiapoptotic genes and impeding tumor promotion. This comprehensive overview emphasizes the potential of Cur as a natural agent for countering aging and degenerative diseases, calling for further dedicated research in this realm.

Abscisic acid activates transcription factor module MdABI5-MdMYBS1 during carotenoid-derived apple fruit coloration.

Carotenoids are major pigments contributing to fruit coloration. We previously reported that the apple (Malus domestica Borkh.) mutant fruits of "Beni Shogun" and "Yanfu 3" show a marked difference in fruit coloration. However, the regulatory mechanism underlying this phenomenon remains unclear. In this study, we determined that carotenoid is the main factor influencing fruit flesh color. We identified an R1-type MYB transcription factor (TF), MdMYBS1, which was found to be highly associated with carotenoids and abscisic acid (ABA) contents of apple fruits. Overexpression of MdMYBS1 promoted, and silencing of MdMYBS1 repressed, β-branch carotenoids synthesis and ABA accumulation. MdMYBS1 regulates carotenoid biosynthesis by directly activating the major carotenoid biosynthetic genes encoding phytoene synthase (MdPSY2-1) and lycopene β-cyclase (MdLCYb). 9-cis-epoxycarotenoid dioxygenase 1 (MdNCED1) contributes to ABA biosynthesis, and MdMYBS1 enhances endogenous ABA accumulation by activating the MdNCED1 promoter. In addition, the basic leucine zipper domain TF ABSCISIC ACID-INSENSITIVE5 (MdABI5) was identified as an upstream activator of MdMYBS1, which promotes carotenoid and ABA accumulation. Furthermore, ABA promotes carotenoid biosynthesis and enhances MdMYBS1 and MdABI5 promoter activities. Our findings demonstrate that the MdABI5-MdMYBS1 cascade activated by ABA regulates carotenoid-derived fruit coloration and ABA accumulation in apple, providing avenues in breeding and planting for improvement of fruit coloration and quality.

Abstract 5853: Regulatory network inference of lung adenocarcinoma drug-tolerant persister cells

Abstract Despite the effectiveness of the latest generation of cancer drugs, partial tumor response and subsequent disease relapse is commonly observed in patients. Recent evidence suggests that treatment resistance emerges from drug-tolerant persister cells (DTPC) that survive through non-genetic tumor cell adaptation. Although DTPC are mostly slow-cycling, a rare subset can re-enter the cell cycle under constitutive presence of treatment. Understanding how DTPC dynamically remodel their molecular portraits at the single-cell level may provide high-resolution insights into the molecular circuits associated with adaptive survival to therapy.Here, we use single-cell RNA sequencing (scRNA-seq) to identify potential mechanisms that promote survival of DTPC and decipher their underlying gene regulatory networks (GRNs), in a model of EGFR-mutant lung adenocarcinoma treated with osimertinib (EGFR inhibitor). Gene expression analysis revealed fewer cell states in DTP compared to treatment-naïve cells (TN). We confirmed the acquisition of DTPC hallmarks (e.g., high epithelial-mesenchymal transition, slow-cycling phenotype, deficient DNA repair). We also identified subpopulations of cells that display intermediate transcriptional states: a pre-existing DTP-like state in a bulk of TN cells, and DTPC with enriched cell cycle signatures, evoking a phenotype of cycling DTPC. To characterize the GRN that govern TN cells, DTPC and the intermediate cell states, we applied the network inference tool PYSCENIC, which associates transcription factors (TFs) to their candidate target genes (TGs) on the basis of the scRNA-seq data and enrichment of TF binding motifs in the genomic regions around TGs. The resulting (GRN) consisted of 5 TF modules clustered on the basis of correlated TF activity.This analysis revealed that, compared to TN cells, DTPC and the intermediate cell states display a marked decreased expression of TFs and TGs involved in mRNA splicing, and more specifically in the initiation of spliceosome assembly through E-complex and A-complex formation. Interestingly, the splicing-related TFs all appear to have affinity for binding to a GCCxC consensus motif or close variant in genes (i.e., SNRPB and SNRPE) that code for key effectors of these initiation complexes. This pilot study highlights that scRNA-seq analyses coupled with inference of regulatory networks might enable the identification of molecular mechanisms that potentially trigger cell state transitions during drug-tolerance. The role of altered mRNA splicing in persistence to EGFR-targeted therapies will be explored experimentally in patient-derived cell lines and 3D organoid cultures. Citation Format: Lisa Chabrier, Camille Leonce, Raphael Schneider, Cyril Degletagne, Pierre Saintigny, Anton Crombach, Sandra Ortiz-Cuaran. Regulatory network inference of lung adenocarcinoma drug-tolerant persister cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5853.

IMPACT OF NF-κB AND NRF2 TRANSCRIPTION FACTOR MODULATORS ON METABOLIC CHARACTERISTICS IN MANDIBLE BONES OF RATS DURING RECOVERY FROM INCOMPLETE FRACTURE UNDER CHRONIC ALCOHOL INTOXICATION

This study aims at investigating the influence of specific modulators of NF-κB and Nrf2 transcription factors on oxidative-nitrosative stress indicators and bone biopolymer depolymerization in mandibular bone following incomplete fracture under chronic alcohol intoxication (CAI). Twenty-eight white male Wistar rats were divided into five groups: Group 1 comprised "falsely injured" rats, while Group 2 underwent incomplete mandibular fracture (IMF) under CAI exposure. Rats in groups 3 and 4 received intraperitoneal injections of ammonium pyrrolidinium dithiocarbamate, an inhibitor of NF-κB activation, in a dose of 76 mg/kg, and dimethyl fumarate, an Nrf2 inducer, in a dose of 15 mg/kg three times a week for 14 days following the modeling of IMF under CAI exposure. The activity of total NO synthase, including its constitutive and inducible isoforms, along with ornithine decarboxylase, and concentrations of peroxynitrites of alkaline and alkaline-earth metals, free hydroxyproline, N-acetylneuraminic, and hexuronic acids were assessed in the homogenate of the standard mandible area using a spectrophotometric method. The findings have demonstrated that the administration of ammonium pyrrolidine dithiocarbamate and dimethyl fumarate notably decreased the activity of NO synthase (primarily its inducible isoform) and the concentration of peroxynitrite in the mandibular bone homogenate, while increasing the activity of ornithine decarboxylase, a key enzyme in polyamine biosynthesis. Furthermore, under experimental conditions, the use of ammonium pyrrolidine dithiocarbamate and dimethyl fumarate limited the depolymerization of bone biopolymers (collagen, glycoproteins, and proteoglycans), thereby facilitating effective reparative osteogenesis.

The OsEIL1-OsWOX11 transcription factor module controls rice crown root development in response to soil compaction.

Optimizing the root architecture of crops is an effective strategy for improving crop yields. Soil compaction is a serious global problem that limits crop productivity by restricting root growth, but the underlying molecular mechanisms are largely unclear. Here, we show that ethylene stimulates rice (Oryza sativa) crown root development in response to soil compaction. First, we demonstrate that compacted soil promotes ethylene production and the accumulation of ETHYLENE INSENSITIVE 3-LIKE 1 (OsEIL1) in rice roots, stimulating crown root primordia initiation and development, thereby increasing crown root number in lower stem nodes. Through transcriptome profiling and molecular analyses, we reveal that OsEIL1 directly activates the expression of WUSCHEL-RELATED HOMEOBOX 11 (OsWOX11), an activator of crown root emergence and growth, and that OsWOX11 mutations delay crown root development, thus impairing the plant's response to ethylene and soil compaction. Genetic analysis demonstrates that OsWOX11 functions downstream of OsEIL1. In summary, our results demonstrate that the OsEIL1-OsWOX11 module regulates ethylene action during crown root development in response to soil compaction, providing a strategy for the genetic modification of crop root architecture and grain agronomic traits.

Long noncoding RNA GATA2AS influences human erythropoiesis by transcription factor and chromatin landscape modulation

AbstractLong noncoding RNAs (lncRNAs) are extensively expressed in eukaryotic cells and have been revealed to be important for regulating cell differentiation. Many lncRNAs have been found to regulate erythroid differentiation in the mouse. However, given the low sequence conservation of lncRNAs between mouse and human, our understanding of lncRNAs in human erythroid differentiation remains incomplete. lncRNAs are often transcribed opposite to protein coding genes and regulate their expression. Here, we characterized a human erythrocyte-expressed lncRNA, GATA2AS, which is transcribed opposite to erythroid transcription regulator GATA2. GATA2AS is a 2080-bp long, primarily nucleus-localized noncoding RNA that is expressed in erythroid progenitor cells and decreases during differentiation. Knockout of GATA2AS in human HUDEP2 erythroid progenitor cells using CRISPR-Cas9 genome editing to remove the transcription start site accelerated erythroid differentiation and dysregulated erythroblast gene expression. We identified GATA2AS as a novel GATA2 and HBG activator. Chromatin isolation by RNA purification showed that GATA2AS binds to thousands of genomic sites and colocalizes at a subset of sites with erythroid transcription factors including LRF and KLF1. RNA pulldown and RNA immunoprecipitation confirmed interaction between GATA2AS and LRF and KLF1. Chromatin immunoprecipitation sequencing (ChIP-seq) showed that knockout of GATA2AS reduces binding of these transcription factors genome wide. Assay for transposase-accessible chromatin sequencing (ATAC-seq) and H3K27ac ChIP-seq showed that GATA2AS is essential to maintain the chromatin regulatory landscape during erythroid differentiation. Knockdown of GATA2AS in human primary CD34+ cells mimicked results in HUDEP2 cells. Overall, our results implicate human-specific lncRNA GATA2AS as a regulator of erythroid differentiation by influencing erythroid transcription factor binding and the chromatin regulatory landscape.

An overview of anti-Hepatitis B virus flavonoids and their mechanisms of action.

Flavonoids, a diverse group of polyphenolic compounds found in various plant-based foods, have garnered attention for their potential in combating Hepatitis B Virus (HBV) infection. Flavonoids have demonstrated promising anti-HBV activities by interfering with multiple stages of the HBV life cycle, making them promising candidates for novel antiviral agents. Certain plant families, such as Theaceae, Asteraceae, Lamiaceae, and Gentianaceae, are of particular interest for their flavonoid-rich members with anti-HBV activities. Evidences, both in vitro and in vivo, supports the anti-HBV potential of flavonoids. These subsets of compound exert their anti-HBV effects through various mechanisms, including inhibiting viral entry, disrupting viral replication, modulating transcription factors, enhancing the immune response, and inducing autophagy. The antioxidant properties of flavonoids play a crucial role in modulating oxidative stress associated with HBV infection. Several flavonoids like epigallocatechin gallate (EGCG), proanthocyanidin (PAC), hexamethoxyflavone, wogonin, and baicalin have shown significant anti-HBV potential, holding promise as therapeutic agents. Synergistic effects between flavonoids and existing antiviral therapies offer a promising approach to enhance antiviral efficacy and reduce drug resistance. Challenges, including limited bioavailability, translation from preclinical studies to clinical practice, and understanding precise targets, need to be addressed. Future research should focus on clinical trials, combination therapies, and the development of flavonoid derivatives with improved bioavailability, and optimizing their effectiveness in managing chronic HBV infections.

Enhancing drought tolerance in cauliflower (Brassica oleracea var. botrytis) by targeting LFY transcription factor modulation via the ethylene precursor, ACCA: an innovative computational approach.

Brassica oleracea var. botrytis is an annual or biennial herbaceous vegetable plant in the Brassicaceae family notable for its edible blossom head. A lot of effort has gone into finding defense-associated proteins in order to better understand how cauliflower and pathogens interact. Endophytes are organisms that live within the host plant and reproduce. Endophytes are bacteria and fungi that reside in plant tissues and can either help or harm the plant. Several species have aided molecular biologists and plant biotechnologists in various ways. Water is essential for a healthy cauliflower bloom. When the weather is hot, this plant dries up, and nitrogen scarcity can be detrimental to cauliflower growth. The study sought to discern plant growth promoting (PGP) compounds that can amplify drought resilience and boost productivity in cauliflower. Investigations were centered on endophytes, microorganisms existing within plant tissues. The dual role of beneficial and detrimental Agrobacterium was scrutinized, particularly emphasizing the ethylene precursor compound, 1-amino-cyclopropane-1-carboxylic acid (ACCA). ACCA possessed salient PGP traits, particularly demonstrating a pronounced enhancement of drought resistance in cauliflower plants. Specifically, during the pivotal marketable curd maturity phase, which necessitates defense against various threats, ACCA showcased a binding energy of -8.74 kcal/mol. ACCA holds a significant promise in agricultural productivity, with its potential to boost drought resistance and cauliflower yield. This could be particularly impactful for regions grappling with high temperatures and possible nitrogen shortages. Future research should explore ACCA's performance under diverse environmental settings and its applicability in other crops.

The Thirty-Fifth Anniversary of K+ Channels in O2 Sensing: What We Know and What We Don’t Know

On the thirty-fifth anniversary of the first description of O2-sensitive K+ channels in the carotid body chemoreceptors O2 sensing remains a salient issue in the literature. Whereas much has been learned about this subject, important questions such as the identity of the specific K+ channel subtype(s) responsible for O2 sensing by chemoreceptors and the mechanism(s) by which their activities are altered by hypoxia have not yet been definitively answered. O2 sensing is a fundamental biological process necessary for the acute and chronic responses to varying environmental O2 levels which allow organisms to adapt to hypoxia. Whereas chronic responses depend on the modulation of hypoxia-inducible transcription factors which determine the expression of numerous genes encoding enzymes, transporters and growth factors, acute responses rely mainly on the dynamic modulation of ion channels by hypoxia, causing adaptive changes in cell excitability, contractility and secretory activity in specialized tissues. The most widely studied oxygen-sensitive ion channels are potassium channels, but oxygen sensing by members of both the calcium and sodium channel families has also been demonstrated. Given the explosion of information on this topic, in this review, we will focus on the mechanisms of physiological oxygen chemotransduction by PO2-dependent K+ channels, with particular emphasis on their function in carotid body chemoreceptor cells (CBCC) and pulmonary artery smooth muscle cells (PASMC), highlighting areas of consensus and controversy within the field. We will first describe the most well-established concepts, those reproduced in multiple laboratories, and then discuss selected observations or questions that remain unresolved, and that limit our progress in this field.