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The WOX (WUSCHEL-related homeobox) is a plant-specific transcription factor involved in plant development and stress response. However, few studies have been reported on the WOX gene in woody plants. In this study, 10 BpWOX genes were isolated from paper mulberry by RACE-PCR and categorized into three clades through phylogenetic analysis, ancient, intermediate and WUS clade. Among them, five members had the transcriptional activity detected by yeast one-hybrid and seven were uniquely localized to the nucleus through green fluorescent protein (GFP) observation. The expression patterns of BpWOX genes in different tissues and under diverse treatments were quantified by the qRT-PCR method. Results showed that BpWUS was expressed in the apical bud, stem and root, BpWOX5 and BpWOX7 functioned only in the root tip, and three BpWOXs regulated leaf development redundantly. BpWOX9 and BpWOX10 were induced by indole-3-acetic acid (IAA) or jasmonic acid (JA), while BpWOX2 was repressed by five phytohormones. Interestingly, most BpWOX genes were responsive to the abiotic stress stimuli of drought, salt, cold, and cadmium (CdCl₂). Together, our study revealed that BpWOXs were functionally divergent during paper mulberry development and environmental adaptation, which might be related to their evolutionary relationships. Our work will benefit the systematic understanding of the precise function of WOX in plant development and environmental stress responses., Competing Interests: The authors declare no conflict of interest.

Paper-bagging is an efficient method to maximize apple skin color, but a relationship between this technique and fruit skin patterning has not been demonstrated. Here, the 'Fuji' fruit with red-striped skin changed to red-blushed skin under re-exposure to light after bag treatment. Higher expression of MdMYB10, a transcription factor that regulates anthocyanin biosynthesis in apples, correlated with increased anthocyanin concentration in bag removal fruit. At the mature stage, a comparison of methylation status in the MdMYB10 promoter revealed that the methylation level in the region from −2585 to −2117 bp was reduced in bag removal fruit, especially for CHG context. It can be regulated by the downregulated expression of DNA methyltransferases such as MdMET, MdCMT, and MdDRM. Our results suggest that the bag removal treatment in this cultivar causes a change in skin patterning from striped to blushed pigmentation by inducing DNA demethylation of MdMYB10. [ABSTRACT FROM AUTHOR]

YABs play an important role in the leaf development of the paper mulberry ( Broussonetia papyrifera ) and of the heterophylly. Thus, we investigated the function of BpYABs. Gene cloning, phylogenetic analysis, motif identification, subcellular localization, transactivation activity assay, qRT-PCR, in situ hybridization, and ectopic expression were used in our study. Six BpYAB s were isolated, and four of them had transcriptional activity. BpYAB1, BpYAB3, BpYAB4, and BpYAB5 were localized to the nucleus. BpYAB1 was only expressed in the flower, while BpYAB6 was not expressed in any detected tissues; the four remaining BpYAB s were expressed in the bud, leaf and flower, and their expression level decreased with leaf development. Further in situ hybridization showed that BpYAB3 and BpYAB5 were expressed in the vascular tissues and lamina, but neither showed the adaxial-abaxial polarity distribution pattern in the mature leaf lamina. Ectopic expression of BpYAB2 , BpYAB3 , BpYAB4 and BpYAB5 induced increased expression of AtWOX1 and caused the leaf of Arabidopsis to become smaller and curl downwards. Ectopic expression also led to shorter siliques and smaller seeds, but not for BpYAB5 . These results suggest that BpYABs have functional divergency and redundancy in regulating leaf and silique development.

UV-B stress can affect plant growth at different levels, and although there is a multitude of evidence confirming the effects of UV-B radiation on plant photosynthesis, there are fewer studies using physiological assays in combination with multi-omics to investigate photosynthesis in alpine plants under stressful environments. Golden 2-like (G2-like/GLK) transcription factors (TFs) are highly conserved during evolution and may be associated with abiotic stress. In this paper, we used Handy-PEA and Imaging-PAM Maxi to detect chlorophyll fluorescence in leaves of Rhododendron chrysanthum Pall. (R. chrysanthum) after UV-B stress, and we also investigated the effect of abscisic acid (ABA) on photosynthesis in plants under stress environments. We used a combination of proteomics, widely targeted metabolomics, and transcriptomics to study the changes of photosynthesis-related substances after UV-B stress. The results showed that UV-B stress was able to impair the donor side of photosystem II (PSII), inhibit electron transfer and weaken photosynthesis, and abscisic acid was able to alleviate the damage caused by UV-B stress to the photosynthetic apparatus. Significant changes in G2-like transcription factors occurred in R. chrysanthum after UV-B stress, and differentially expressed genes localized in the Calvin cycle were strongly correlated with members of the G2-like TF family. Multi-omics assays and physiological measurements together revealed that G2-like TFs can influence photosynthesis in R. chrysanthum under UV-B stress by regulating the Calvin cycle. This paper provides insights into the study of photosynthesis in plants under stress, and is conducive to the adoption of measures to improve photosynthesis in plants under stress to increase yield. [ABSTRACT FROM AUTHOR]

Isothiocyanates (ITCs) belong to a group of natural products that possess a highly reactive electrophilic −N=C=S functional group. They are stored in plants as precursor molecules, glucosinolates, which are processed by the tyrosinase enzyme upon plant tissue damage to release ITCs, along with other products. Isolated from broccoli, sulforaphane is by far the most studied antioxidant ITC, acting primarily through the induction of a transcription factor, the nuclear factor erythroid 2–related factor 2 (Nrf2), which upregulates downstream antioxidant genes/proteins. Paradoxically, sulforaphane, as a pro-oxidant compound, can also increase the levels of reactive oxygen species, a mechanism which is attributed to its anticancer effect. Beyond highlighting the common pro-oxidant and antioxidant effects of sulforaphane, the present paper was designed to assess the diverse anti-inflammatory mechanisms reported to date using a variety of in vitro and in vivo experimental models. Sulforaphane downregulates the expression of pro-inflammatory cytokines, chemokines, adhesion molecules, cycloxyhenase-2, and inducible nitric oxide synthase. The signalling pathways of nuclear factor κB, activator protein 1, sirtuins 1, silent information regulator sirtuin 1 and 3, and microRNAs are among those affected by sulforaphane. These anti-inflammatory actions are sometimes due to direct action via interaction with the sulfhydryl structural moiety of cysteine residues in enzymes/proteins. The following are among the topics discussed in this paper: paradoxical signalling pathways such as the immunosuppressant or immunostimulant mechanisms; crosstalk between the oxidative and inflammatory pathways; and effects dependent on health and disease states. [ABSTRACT FROM AUTHOR]

Biotic and abiotic stresses have already seriously restricted the growth and development of Pinus massoniana , thereby influencing the quality and yield of its wood and turpentine. Recent studies have shown that C2H2 zinc finger protein transcription factors play an important role in biotic and abiotic stress response. However, the members and expression patterns of C2H2 TFs in response to stresses in P. massoniana have not been performed. In this paper, 57 C2H2 zinc finger proteins of P. massoniana were identified and divided into five subgroups according to a phylogenetic analysis. In addition, six Q-type PmC2H2-ZFPs containing the plant-specific motif 'QALGGH' were selected for further study under different stresses. The findings demonstrated that PmC2H2-ZFPs exhibit responsiveness towards various abiotic stresses, including drought, NaCl, ABA, PEG, H 2 O 2 , etc., as well as biotic stress caused by the pine wood nematode. In addition, PmC2H2-4 and PmC2H2-20 were nuclear localization proteins, and PmC2H2-20 was a transcriptional activator. PmC2H2-20 was selected as a potential transcriptional regulator in response to various stresses in P. massoniana . These findings laid a foundation for further study on the role of PmC2H2-ZFPs in stress tolerance.

Transcription factors (TFs) are crucial in modulating gene expression and sculpting cellular and organismal phenotypes. The identification of TF-target gene interactions is pivotal for comprehending molecular pathways and disease etiologies but has been hindered by the demanding nature of traditional experimental approaches. This paper introduces a novel web application and package utilizing the R program, which predicts TF-target gene relationships and vice versa. Our application integrates the predictive power of various bioinformatic tools, leveraging their combined strengths to provide robust predictions. It merges databases for enhanced precision, incorporates gene expression correlation for accuracy, and employs pan-tissue correlation analysis for context-specific insights. The application also enables the integration of user data with established resources to analyze TF-target gene networks. Despite its current limitation to human data, it provides a platform to explore gene regulatory mechanisms comprehensively. This integrated, systematic approach offers researchers an invaluable tool for dissecting the complexities of gene regulation, with the potential for future expansions to include a broader range of species., Competing Interests: The author declares no conflicts of interest.

The extracellular matrix is a complex network of proteins and other molecules that are essential for the support, integrity, and structure of cells and tissues within the human body. The genes ZNF469 and PRDM5 each produce extracellular-matrix-related proteins that, when mutated, have been shown to result in the development of brittle cornea syndrome. This dysfunction results from aberrant protein function resulting in extracellular matrix disruption. Our group recently identified and published the first known associations between variants in these genes and aortic/arterial aneurysms and dissection diseases. This paper delineates the proposed effects of mutated ZNF469 and PRDM5 on various essential extracellular matrix components, including various collagens, TGF-B, clusterin, thrombospondin, and HAPLN-1, and reviews our recent reports associating single-nucleotide variants to these genes' development of aneurysmal and dissection diseases.

The Whirly (WHY) gene family, functioning as transcription factors, plays an essential role in the regulation of plant metabolic responses, which has been demonstrated across multiple species. However, the WHY gene family and its functions in soybean remains unclear. In this paper, we conducted genome-wide screening and identification to characterize the WHY gene family. Seven WHY members were identified and randomly distributed across six chromosomes. The phylogenetic evolutionary tree of WHY genes in soybean and other species was divided into five clades. An in-depth analysis revealed that segmental duplications significantly contributed to the expansion of GmWHYs, and the GmWHY gene members may have experienced evolutionary pressure for purifying selection in soybeans. The analysis of promoter Cis-elements in GmWHYs suggested their potential significance in addressing diverse stress conditions. The expression patterns of GmWHYs exhibited tissue-specific variations throughout the different stages of soybean development. Additionally, six GmWHY genes exhibited different responses to low phosphate stress. These findings will provide a theoretical basis and valuable reference for the future exploration of WHY gene function. [ABSTRACT FROM AUTHOR]

Although our skin is not the primary visual organ in humans, it acts as a light sensor, playing a significant role in maintaining our health and overall well-being. Thanks to the presence of a complex and sophisticated optotransduction system, the skin interacts with the visible part of the electromagnetic spectrum and with ultraviolet (UV) radiation. Following a brief overview describing the main photosensitive molecules that detect specific electromagnetic radiation and their associated cell pathways, we analyze their impact on physiological functions such as melanogenesis, immune response, circadian rhythms, and mood regulation. In this paper, we focus on 6-formylindolo[3,2-b]carbazole (FICZ), a photo oxidation derivative of the essential amino acid tryptophan (Trp). This molecule is the best endogenous agonist of the Aryl hydrocarbon Receptor (AhR), an evolutionarily conserved transcription factor, traditionally recognized as a signal transducer of both exogenous and endogenous chemical signals. Increasing evidence indicates that AhR is also involved in light sensing within the skin, primarily due to its ligand FICZ, which acts as both a chromophore and a photosensitizer. The biochemical reactions triggered by their interaction impact diverse functions and convey crucial data to our body, thus adding a piece to the complex puzzle of pathways that allow us to decode and elaborate environmental stimuli. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with pediatric liver cancers hepatoblastoma and hepatocellular carcinoma very often develop lung metastases. These cancers can present with lung metastases and are at higher risk of relapse. Although cisplatin is very effective at clearing lung metastases, they can still relapse. Therefore, there is an urgent need to develop therapeutic approaches to prevent the development of lung metastases in patients with pediatric liver cancers. In this paper, we show that the metastatic microenvironment of HBL and HCC patients contains a heterogeneous cell population that formed tumor clusters. We found that both fresh primary tumors and generated primary cell cultures had increased the expression of HDAC1, a histone deacetylase, and the transcription factor Sp5. Sp5 and HDAC1 work in tandem by transporting HDAC1 to the promoters of genes and changing their expression. We analyzed the effects of the HDAC inhibitor, SAHA, on the metastasis-initiating cells in combination with cisplatin. We found that HDAC inhibition increases the efficacy of cisplatin to eliminate these metastasis-initiating cells. The pediatric liver cancers, hepatoblastoma and hepatocellular carcinoma, are dangerous cancers which often spread to the lungs. Although treatments with cisplatin significantly improve outcomes, cisplatin may not eliminate metastasis-initiating cells. Our group has recently shown that the metastatic microenvironments of hepatoblastoma contain Cancer Associated Fibroblasts (CAFs) and neuron-like cells, which initiate cancer spread from liver to lungs. In this study, we found that these cells express high levels of HDAC1; therefore, we examined if histone deacetylase inhibition improves cisplatin anti-proliferative effects and reduces the formation of tumor clusters in pediatric liver cancer metastatic microenvironments. Methods: New cell lines were generated from primary hepatoblastoma liver tumors (hbl) and lung metastases (LM) of HBL patients. In addition, cell lines were generated from hepatocellular neoplasm, not otherwise specified (HCN-NOS) tumor samples, and hcc cell lines. Hbl, LM and hcc cells were treated with cisplatin, SAHA or in combination. The effect of these drugs on the number of cells, formation of tumor clusters and HDAC1-Sp5-p21 axis were examined. Results: Both HBL and HCC tissue specimens have increased HDAC1-Sp5 pathway activation, recapitulated in cell lines generated from the tumors. HDAC inhibition with vorinostat (SAHA) increases cisplatin efficacy to eliminate CAFs in hbl and in hcc cell lines. Although the neuron-like cells survive the combined treatments, proliferation was inhibited. Notably, combining SAHA with cisplatin overcame cisplatin resistance in an LM cell line from an aggressive case with multiple metastases. Underlying mechanisms of this enhanced inhibition include suppression of the HDAC1-Sp5 pathway and elevation of an inhibitor of proliferation p21. Similar findings were found with gemcitabine treatments suggesting that elimination of proliferative CAFs cells is a key event in the inhibition of mitotic microenvironment. Conclusions: Our studies demonstrate the synergistic benefits of HDAC inhibition and cisplatin to eliminate metastasis-initiating cells in pediatric liver cancers. [ABSTRACT FROM AUTHOR]

The exact identification of promoter sequences remains a serious problem in computational biology, as the promoter prediction algorithms under development continue to produce false-positive results. Therefore, to fully assess the validity of predicted sequences, it is necessary to perform a comprehensive test of their properties, such as the presence of downstream transcribed DNA regions behind them, or chromatin accessibility for transcription factor binding. In this paper, we examined the promoter sequences of chromosome 1 of the rice Oryza sativa genome from the Database of Potential Promoter Sequences predicted using a mathematical algorithm based on the derivation and calculation of statistically significant promoter classes. In this paper TATA motifs and cis-regulatory elements were identified in the predicted promoter sequences. We also verified the presence of potential transcription start sites near the predicted promoters by analyzing CAGE-seq data. We searched for unannotated transcripts behind the predicted sequences by de novo assembling transcripts from RNA-seq data. We also examined chromatin accessibility in the region of the predicted promoters by analyzing ATAC-seq data. As a result of this work, we identified the predicted sequences that are most likely to be promoters for further experimental validation in an in vivo or in vitro system. [ABSTRACT FROM AUTHOR]

It is known that V-set and immunoglobulin domain containing 1 (VSIG1) is a cell–cell adhesion molecule that can serve as an indicator of better survival in patients with gastric cancer. Its interaction with cytoplasmic thyroid transcription factor 1 (TTF-1) has been hypothesized to characterize gastric-type HCC, but its clinical importance is far from understood. As VSIG1 has also been supposed to be involved in the epithelial–mesenchymal transition (EMT) phenomenon, we checked for the first time in the literature the supposed interaction between VSIG1, TTF-1, and Vimentin (VIM) in HCCs. Immunohistochemical (IHC) stains were performed on 217 paraffin-embedded tissue samples that included tumor cells and normal hepatocytes, which served as positive internal controls. VSIG1 positivity was seen in 113 cases (52.07%). In 71 out of 217 HCCs (32.71%), simultaneous positivity for VSIG1 and TTF-1 was seen, being more specific for G1/G2 carcinomas with a trabecular architecture and a longer OS (p = 0.004). A negative association with VIM was revealed (p < 0.0001). Scirrhous-type HCC proved negative for all three examined markers. The present paper validates the hypothesis of the existence of a gastric-type HCC, which shows a glandular-like architecture and is characterized by double positivity for VSIG1 and TTF-1, vimentin negativity, and a significant OS. [ABSTRACT FROM AUTHOR]

RAMOSA1 (RA1) is a Cys2-His2-type (C2H2) zinc finger transcription factor that controls plant meristem fate and identity and has played an important role in maize domestication. Despite its importance, the origin of RA1 is unknown, and the evolution in plants is only partially understood. In this paper, we present a well-resolved phylogeny based on 73 amino acid sequences from 48 embryophyte species. The recovered tree topology indicates that, during grass evolution, RA1 arose from two consecutive SUPERMAN duplications, resulting in three distinct grass sequence lineages: RA1-like A, RA1-like B, and RA1; however, most of these copies have unknown functions. Our findings indicate that RA1 and RA1-like play roles in the nucleus despite lacking a traditional nuclear localization signal. Here, we report that copies diversified their coding region and, with it, their protein structure, suggesting different patterns of DNA binding and protein–protein interaction. In addition, each of the retained copies diversified regulatory elements along their promoter regions, indicating differences in their upstream regulation. Taken together, the evidence indicates that the RA1 and RA1-like gene families in grasses underwent subfunctionalization and neofunctionalization enabled by gene duplication. [ABSTRACT FROM AUTHOR]

Chromatin modifications play a crucial role in the regulation of gene expression. The repressor element-1 (RE1) silencing transcription factor (REST), also known as neuron-restrictive silencer factor (NRSF) and X2 box repressor (XBR), was found to regulate gene transcription by binding to chromatin and recruiting chromatin-modifying enzymes. Earlier studies revealed that REST plays an important role in the development and disease of the nervous system, mainly by repressing the transcription of neuron-specific genes. Subsequently, REST was found to be critical in other tissues, such as the heart, pancreas, skin, eye, and vascular. Dysregulation of REST was also found in nervous and non-nervous system cancers. In parallel, multiple strategies to target REST have been developed. In this paper, we provide a comprehensive summary of the research progress made over the past 28 years since the discovery of REST, encompassing both physiological and pathological aspects. These insights into the effects and mechanisms of REST contribute to an in-depth understanding of the transcriptional regulatory mechanisms of genes and their roles in the development and progression of disease, with a view to discovering potential therapeutic targets and intervention strategies for various related diseases.

Simple Summary: Glioblastoma is an aggressive brain cancer. Despite progress made in cancer research, patients diagnosed with glioblastomas continue to have a poor rate of survival. Lipidomics is a field of study that seeks to comprehend the structure and function of lipids, otherwise known as fats. Glioblastomas have demonstrated imbalance in lipids, and, therefore, lipidomics shows promise as an avenue to better understand glioblastomas. This paper reviews the literature on lipidomics in glioblastomas and suggests future directions for lipidomic research into the diagnosis, prognosis, and treatment of glioblastomas. Glioblastoma is the most aggressive primary brain malignancy in adults, and has a survival duration of approximately 15 months. First line treatment involves surgical resection, chemotherapy, and radiation, but despite the multi-pronged approach and advances in cancer research, glioblastoma remains devastating with a high mortality rate. Lipidomics is an emerging discipline that studies lipid pathways and characteristics, and is a promising field to understand biochemical mechanisms. In glioblastoma, disrupted lipid homeostasis has been reported in the literature. A thorough understanding of serum lipidomics may offer ways to better understand glioblastoma biomarkers, prognosis, and treatment options. Here, we review the literature, offering future directions for lipidomics research in glioblastomas. [ABSTRACT FROM AUTHOR]

Abiotic stress is an adverse environmental factor that severely affects plant growth and development, and plants have developed complex regulatory mechanisms to adapt to these unfavourable conditions through long-term evolution. In recent years, many transcription factor families of genes have been identified to regulate the ability of plants to respond to abiotic stresses. Among them, the AP2/ERF (APETALA2/ethylene responsive factor) family is a large class of plant-specific proteins that regulate plant response to abiotic stresses and can also play a role in regulating plant growth and development. This paper reviews the structural features and classification of AP2/ERF transcription factors that are involved in transcriptional regulation, reciprocal proteins, downstream genes, and hormone-dependent signalling and hormone-independent signalling pathways in response to abiotic stress. The AP2/ERF transcription factors can synergise with hormone signalling to form cross-regulatory networks in response to and tolerance of abiotic stresses. Many of the AP2/ERF transcription factors activate the expression of abiotic stress-responsive genes that are dependent or independent of abscisic acid and ethylene in response to abscisic acid and ethylene. In addition, the AP2/ERF transcription factors are involved in gibberellin, auxin, brassinosteroid, and cytokinin-mediated abiotic stress responses. The study of AP2/ERF transcription factors and interacting proteins, as well as the identification of their downstream target genes, can provide us with a more comprehensive understanding of the mechanism of plant action in response to abiotic stress, which can improve plants' ability to tolerate abiotic stress and provide a more theoretical basis for increasing plant yield under abiotic stress. [ABSTRACT FROM AUTHOR]

Cystic Fibrosis (CF) is present due to mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, the most frequent variant being p.phe508del. The CFTR protein is a chloride (Cl-) channel which is defective and almost absent of cell membranes when the p.Phe508del mutation is present. The p.Phe508del-CFTR protein is retained in the endoplasmic reticulum (ER) and together with inflammation and infection triggers the Unfolded Protein Response (UPR). During the UPR, the Activating Transcription Factor 6 (ATF6) is activated with cleavage and then decreases the expression of p.Phe508del-CFTR. We have previously shown that the inhibition of the activation of ATF6 alleviates the p.Phe508del-CFTR defects in cells overexpressing the mutated protein. In the present paper, our aim was to inhibit the cleavage of ATF6, and thus its activation in a human bronchial cell line with endogenous p.Phe508del-CFTR expression and in bronchial cells from patients, to be more relevant to CF. This was achieved by inhibiting the protease MBTP1 which is responsible for the cleavage of ATF6. We show here that this inhibition leads to increased mRNA and p.Phe508del-CFTR expression and, consequently, to increased Cl-efflux. We also explain the mechanisms linked to these increases with the modulation of genes when MBTP1 is inhibited. Indeed, RT-qPCR assays show that genes such as HSPA1B, CEBPB, VIMP, PFND2, MAPK8, XBP1, INSIG1, and CALR are modulated. In conclusion, we show that the inhibition of MBTP1 has a beneficial effect in relevant models to CF and that this is due to the modulation of genes involved in the disease. [ABSTRACT FROM AUTHOR]

Transcription factors (TFs) and microRNAs (miRNAs) are co-actors in genome-scale decoding and regulatory networks, often targeting common genes. To discover the symmetries and invariants of the transcription and regulation at the scale of the genome, in this paper, we introduce tools of infinite group theory and of algebraic geometry to describe both TFs and miRNAs. In TFs, the generator of the group is a DNA-binding domain while, in miRNAs, the generator is the seed of the sequence. For such a generated (infinite) group π , we compute the S L (2 , C) character variety, where S L (2 , C) is simultaneously a 'space-time' (a Lorentz group) and a 'quantum' (a spin) group. A noteworthy result of our approach is to recognize that optimal regulation occurs when π looks similar to a free group F r ( r = 1 to 3) in the cardinality sequence of its subgroups, a result obtained in our previous papers. A non-free group structure features a potential disease. A second noteworthy result is about the structure of the Groebner basis G of the variety. A surface with simple singularities (such as the well known Cayley cubic) within G is a signature of a potential disease even when π looks similar to a free group F r in its structure of subgroups. Our methods apply to groups with a generating sequence made of two to four distinct DNA/RNA bases in { A , T / U , G , C } . We produce a few tables of human TFs and miRNAs showing that a disease may occur when either π is away from a free group or G contains surfaces with isolated singularities. [ABSTRACT FROM AUTHOR]

Bones serve mechanical and defensive functions, as well as regulating the balance of calcium ions and housing bone marrow.. The qualities of bones do not remain constant. Instead, they fluctuate throughout life, with functions increasing in some situations while deteriorating in others. The synchronization of osteoblast-mediated bone formation and osteoclast-mediated bone resorption is critical for maintaining bone mass and microstructure integrity in a steady state. This equilibrium, however, can be disrupted by a variety of bone pathologies. Excessive osteoclast differentiation can result in osteoporosis, Paget's disease, osteolytic bone metastases, and rheumatoid arthritis, all of which can adversely affect people's health. Osteoclast differentiation is regulated by transcription factors NFATc1, MITF, C/EBPα, PU.1, NF-κB, and c-Fos. The transcriptional activity of osteoclasts is largely influenced by developmental and environmental signals with the involvement of co-factors, RNAs, epigenetics, systemic factors, and the microenvironment. In this paper, we review these themes in regard to transcriptional regulation in osteoclastogenesis. [ABSTRACT FROM AUTHOR]

Putative methyltranferase LaeA and LaeA-like proteins, conserved in many filamentous fungi, regulate fungal growth, development, virulence, the biosynthesis of secondary metabolites, and the production of cellulolytic enzymes. Penicillium oxaliucm is a typical fungus that produces cellulolytic enzymes. In this study, we reported the biological function of eight putative methyltransferases (PoMtr23C/D/E/F/G/H and PoMtr25A/B) containing a methyltransf_23 or methyltransf_25 domain, with a focus on their roles in the production of cellulolytic enzymes. In P. oxalicum, various methyltransferase genes displayed different transcriptional levels. The genes Pomtr23C and Pomtr25A exhibited high transcriptional levels, while Pomtr23D/E/F/G/H and Pomtr25B were transcribed constantly at low levels. The gene deletion mutants (Δmtr23C/D/E/F/G/H and Δmtr25A/B) were constructed. Various mutants have different patterns in cellulolytic enzyme production. Compared to the WT, the largest increase in filter paper activity (FPA, indicating total cellulase activity) was observed in the Δmtr23G mutant, the only mutant with a cellulolytic halo surrounding the colony. Three mutants (Δmtr23C/D and Δmtr25A) also showed increased cellulolytic enzyme production. The Δmtr23E and Δmtr25B mutants displayed decreased FPA activity, while the Δmtr23F and Δmtr23H mutants displayed similar patterns of cellulolytic enzyme production compared with the WT. The assay of transcriptional levels of cellobiohydrolase gene Pocbh1 and β-1,4-endoglucanase Poeg1 supported that higher cellulolytic gene transcription resulted in higher production of cellulolytic enzymes, and vice versa. The transcriptional levels of two transcription factors, activator XlnR and repressor CreA, were measured. The high transcription level of the PoxlnR gene in the Δmtr23D mutant should be one reason for the increased transcription of its cellulolytic enzyme gene. Both XlnR and CreA transcriptional levels increased in the Δmtr23G mutant, but the former showed a more significant increase than the latter, indicating that the activation effect predominated. The PoMtr25A is localized in the nucleus. The catalytic subunit SNF2 of the SWI/SNF chromatin-remodeling complex was found as one of the interacting proteins of PoMtr25A via tandem affinity purification coupled with mass spectrometry. PoMtr25A may affect not only the transcription of repressor CreA but also by recruiting SWI/SNF complexes that affect chromatin structure, thereby regulating the transcription of target genes. [ABSTRACT FROM AUTHOR]

The nuclear membrane serves a critical role in protecting the contents of the nucleus and facilitating material and signal exchange between the nucleus and cytoplasm. While extensive research has been dedicated to topics such as nuclear membrane assembly and disassembly during cell division, as well as interactions between nuclear transmembrane proteins and both nucleoskeletal and cytoskeletal components, there has been comparatively less emphasis on exploring the regulation of nuclear morphology through nuclear membrane integrity. In particular, the role of type II integral proteins, which also function as transcription factors, within the nuclear membrane remains an area of research that is yet to be fully explored. The integrity of the nuclear membrane is pivotal not only during cell division but also in the regulation of gene expression and the communication between the nucleus and cytoplasm. Importantly, it plays a significant role in the development of various diseases. This review paper seeks to illuminate the biomolecules responsible for maintaining the integrity of the nuclear membrane. It will delve into the mechanisms that influence nuclear membrane integrity and provide insights into the role of type II membrane protein transcription factors in this context. Understanding these aspects is of utmost importance, as it can offer valuable insights into the intricate processes governing nuclear membrane integrity. Such insights have broad-reaching implications for cellular function and our understanding of disease pathogenesis. [ABSTRACT FROM AUTHOR]

The MYB transcription factor family is one of the largest families of plant transcription factors (TFs), and it plays a vital role in the entire process of a plant's growth and development. Well known in China, Eucommia ulmoides (E. ulmoides) produces a form of natural rubber called Eucommia ulmoides gum (EUG). Nevertheless, there is little research on the evolutionary history and expression patterns of its MYBs, as well as on the regulation of EUG by MYB TFs. This research provides a comprehensive description, classification, and potential functional analysis of the EuMYB gene family. A total of 119 MYB members of E. ulmoides were identified based on the whole genome sequencing data, and their gene structure, phylogenetics, chromosome location, conserved motifs, etc., were analyzed. Based on the phylogenetic tree results, EuMYBs could be divided into 35 sub-groups. In addition, chromosomal localization and collinearity analysis revealed the heterogeneous distribution of the MYB family in the E. ulmoides' genome, indicating the expansion of its gene family. Moreover, promoter cis-acting elements showed that the promoter contained abundant light-responsive elements, anaerobic-induction-responsive elements, and abscisic-acid-responsive elements. A co-expression regulatory network between the EUG biosynthesis genes and the EuMYBs was built. Meanwhile, regarding the six EuMYBs with high expression in the gum-forming tissues selected that correlated with the farnesyl diphosphate synthase (FPS1) structural gene, RT-qPCR experiments showed a possible regulatory relationship between EuMYBs and FPS1, which played an important role in EUG biosynthesis. In conclusion, this paper defines a research gap and lays a foundation for further studies on the biological functions of EuMYBs. [ABSTRACT FROM AUTHOR]

This document, published in the International Journal of Molecular Sciences, discusses the concept of dual function molecules in cell biology. It explains that many molecules in cells can have opposing roles depending on their context, pathway, or location within the cell. The document provides examples of proteins with dual functions, such as p53 and cyclin-dependent kinase inhibitors. It also explores the dual roles of factors like c-Jun-NH(2)-terminal kinase (JNK), reactive oxygen species (ROS), and glucocorticoid treatment in cancer cells. The authors conclude that understanding these dual functions is crucial for studying cell fate decisions. [Extracted from the article]

Simple Summary: Melanoma is the deadliest form of skin cancer, with the BRAF(V600E) mutation being the most prevalent driver mutation. Despite targeted therapies against BRAF(V600E) mutation and immune checkpoint-blocking antibodies providing treatment options for patients, the heterogeneous nature of melanoma significantly limits treatment efficacy. Understanding diverse regulatory mechanisms in melanoma will shed light on improving the current treatment modalities. In this study, we explored the function of a novel transcriptional activator, TCF12, in melanoma progression. We found that the expression level of TCF12 is elevated as melanoma progresses, and high expression is strongly associated with poor survival outcomes in melanoma patients. Functionally, TCF12 enhances melanoma proliferation and metastasis, as well as the sensitivity to BRAF(V600E)-targeted therapy. Mechanistically, TGFB2 is the direct transcriptional target of TCF12, mediating its pro-tumorigenic effects. Collectively, our study supported the oncogenic functions of TCF12 in melanoma, revealing it as a potential target to improve the efficacy of BRAF(V600E)-targeted therapy. As one of the most common malignant tumors, melanoma is a serious threat to human health. More than half of melanoma patients have a BRAF mutation, and 90% of them have a BRAF(V600E) mutation. There is a targeted therapy for patients using a BRAF(V600E) inhibitor. However, no response to treatment is generally inevitable due to the heterogeneity of melanoma. Coupled with its high metastatic character, melanoma ultimately leads to poor overall survival. This study aimed to explore the possible mechanisms of melanoma metastasis and identify a more effective method for the treatment of melanoma. In this paper, we report that TCF12 expression is higher in melanoma, especially in metastatic tumors, through analyzing data from TCGA. Then, cell proliferation, colony formation, and transwell assays show that the upregulated expression of TCF12 can promote proliferation and metastasis of melanoma cells in vitro. The same result is confirmed in the subcutaneous tumor formation assay. Moreover, TGFB2 is identified as a direct downstream target of TCF12 by RNA-seq, qPCR, immunoblotting, ChIP, and a dual luciferase reporting assay. Interestingly, depletion of TCF12 can sensitize melanoma to BRAF inhibition both in vitro and in vivo. Overall, our results demonstrate that TCF12 promotes melanoma progression and can be a potential tumor therapeutic target. [ABSTRACT FROM AUTHOR]

Suppressor of mother against decapentaplegic (SMAD) family proteins are central to one of the most versatile cytokine signalling pathways in metazoan biology, the transforming growth factor-β (TGF-β) pathway. The TGF-β pathway is widely known for its dual role in cancer progression as both an inhibitor of tumour cell growth and an inducer of tumour metastasis. This is mainly mediated through SMAD proteins and their cofactors or regulators. SMAD proteins act as transcription factors, regulating the transcription of a wide range of genes, and their rich post-translational modifications are influenced by a variety of regulators and cofactors. The complex role, mechanisms, and important functions of SMAD proteins in tumours are the hot topics in current oncology research. In this paper, we summarize the recent progress on the effects and mechanisms of SMAD proteins on tumour development, diagnosis, treatment and prognosis, and provide clues for subsequent research on SMAD proteins in tumours. [ABSTRACT FROM AUTHOR]

Simple Summary: New treatments that utilize targeted therapeutic agents or invigorations of the host immune system to destroy cancer cells are not effective against all cancers or responding patients. The mechanism underlying this failure is the ability of cancer cells to escape destruction and remain resistant to therapy. Understanding the gene products that make cancer cells resistant is beneficial in developing new drugs that inhibit resistant factors. One factor controlling the resistance in cancer cells is the gene regulator or transcription factor (TF) Yin Yang 1 (YY1). High levels of YY1 were detected in resistant cancer cells, while the inhibition restored sensitivities to cytotoxic therapies. This review discusses how YY1 overexpression regulates death protective proteins that control cancer cell resistance. Targeting YY1 in cancer cells for its inhibition or targeting its protective proteins will reverse resistance and allow for cancer cells to respond to therapies, tumor regression and the prolongation of survival. Cancer is a leading cause of death among the various diseases encountered in humans. Cancer is not a single entity and consists of numerous different types and subtypes that require various treatment regimens. In the last decade, several milestones in cancer treatments were accomplished, such as specific targeting agents or revitalizing the dormant anti-tumor immune response. These milestones have resulted in significant positive clinical responses as well as tumor regression and the prolongation of survival in subsets of cancer patients. Hence, in non-responding patients and non-responding relapsed patients, cancers develop intrinsic mechanisms of resistance to cell death via the overexpression of anti-apoptotic gene products. In parallel, the majority of resistant cancers have been reported to overexpress a transcription factor, Yin Yang 1 (YY1), which regulates the chemo-immuno-resistance of cancer cells to therapeutic anticancer cytotoxic agents. The relationship between the overexpression of YY1 and several anti-apoptotic gene products, such as B-cell lymphoma 2 protein (Bcl-2), B-cell lymphoma extra-large (Bcl-xL), myeloid cell leukemia 1 (Mcl-1) and survivin, is investigated in this paper. The findings demonstrate that these anti-apoptotic gene products are regulated, in part, by YY1 at the transcriptional, epigenetic, post-transcriptional and translational levels. While targeting each of the anti-apoptotic gene products individually has been examined and clinically tested for some, this targeting strategy is not effective due to compensation by other overexpressed anti-apoptotic gene products. In contrast, targeting YY1 directly, through small interfering RNAs (siRNAs), gene editing or small molecule inhibitors, can be therapeutically more effective and generalized in YY1-overexpressed resistant cancers. [ABSTRACT FROM AUTHOR]

A genome-wide analysis for two families of key transcription factors (TF; WRKY and NAC) involved in drought response revealed 46 WRKY and 66 NAC members of the Carica papaya genome. A phylogenetic analysis grouped the CpWRKY proteins into three groups (I, II a, b, c, d, e and III), while the CpNAC proteins were clustered into 15 groups. The conserved domains, chromosomal localization and promoter cis-acting elements were also analyzed. In addition, from a previous transcriptome study of two contrasting genotypes in response to 14 days of water deficit stress (WDS), we found that 29 of the 46 CpWRKYs genes and 25 of the 66 CpNACs genes were differentially expressed in response to the WDS. In the present paper, the native wild genotype (WG) (collected in its center of origin) consistently showed a higher expression (transcripts per million; TPM and fold change; FC) than the commercial genotype (CG) in almost all the members of the CpWRKY and CpNAC gene families. To corroborate this, we selected CpWRKY50 and CpNAC83.1 for further evaluation by RT-qPCR. Consistently, the WG showed higher relative expression levels (REL) after 14 days of WDS than the CG, in both the leaves and roots. The results suggest that the CpWRKY and CpNAC TF families are important for drought tolerance in this species. The results may also suggest that, during the domestication process, the ability of the native (wild) C. papaya genotypes to respond to drought (including the overexpression of the CpWRKY and CpNAC genes) was somehow reduced in the current commercial genotypes. [ABSTRACT FROM AUTHOR]

The NF-κB-signaling pathway plays a crucial role in cancer progression, including muscle-derived cancers such as rhabdomyosarcoma or sarcoma. Several natural compounds have been studied for their ability to alter NF-κB signaling in these types of cancers. This review paper summarizes the current knowledge on the effects of natural compounds, including curcumin, resveratrol, quercetin, epigallocatechin-3-gallate, and berberine, on NF-κB signaling in muscle-derived cancers. These compounds have been shown to inhibit NF-κB signaling in rhabdomyosarcoma cells through various mechanisms, such as inhibiting the activation of the IKK complex and the NF-κB transcription factor. These findings suggest that natural compounds could be potential therapeutic agents for muscle-derived cancers. However, further research is needed to fully understand their mechanisms of action and potential clinical applications. [ABSTRACT FROM AUTHOR]

Abundant experimental data suggest that hydrogen sulfide (H2S) is related to the pathophysiology of Diabetes Mellitus (DM). Multiple molecular mechanisms, including receptors, membrane ion channels, signalingmolecules, enzymes, and transcription factors, are known to be responsible for the H2S biological actions; however, H2S is not fully documented as a gaseous signaling molecule interfering with DM and vascular-linked pathology. In recent decades, multiple approaches regarding therapeutic exploitation of H2S have been identified, either based on H2S exogenous apport or on its modulated endogenous biosynthesis. This paper aims to synthesize and systematize, as comprehensively as possible, the recent literature-related data regarding the therapeutic/rehabilitative role of H2S in DM. This review was conducted following the "Preferred reporting items for systematic reviews and meta-analyses" (PRISMA) methodology, interrogating five international medically renowned databases by specific keyword combinations/"syntaxes" used contextually, over the last five years (2017–2021). The respective search/filtered and selection methodology we applied has identified, in the first step, 212 articles. After deploying the next specific quest steps, 51 unique published papers qualified for minute analysis resulted. To these bibliographic resources obtained through the PRISMA methodology, in order to have the best available information coverage, we added 86 papers that were freely found by a direct internet search. Finally, we selected for a connected meta-analysis eight relevant reports that included 1237 human subjects elicited from clinical trial registration platforms. Numerous H2S releasing/stimulating compounds have been produced, some being used in experimental models. However, very few of them were further advanced in clinical studies, indicating that the development of H2S as a therapeutic agent is still at the beginning. [ABSTRACT FROM AUTHOR]

Chromatin features can reveal tissue-specific TF-DNA binding, which leads to a better understanding of many critical physiological processes. Accurately identifying TF-DNA bindings and constructing their relationships with chromatin features is a long-standing goal in the bioinformatic field. However, this has remained elusive due to the complex binding mechanisms and heterogeneity among inputs. Here, we have developed the GHTNet (General Hybrid Transformer Network), a transformer-based model to predict TF-DNA binding specificity. The GHTNet decodes the relationship between tissue-specific TF-DNA binding and chromatin features via a specific input scheme of alternative inputs and reveals important gene regions and tissue-specific motifs. Our experiments show that the GHTNet has excellent performance, achieving about a 5% absolute improvement over existing methods. The TF-DNA binding mechanism analysis shows that the importance of TF-DNA binding features varies across tissues. The best predictor is based on the DNA sequence, followed by epigenomics and shape. In addition, cross-species studies address the limited data, thus providing new ideas in this case. Moreover, the GHTNet is applied to interpret the relationship among TFs, chromatin features, and diseases associated with AD46 tissue. This paper demonstrates that the GHTNet is an accurate and robust framework for deciphering tissue-specific TF-DNA binding and interpreting non-coding regions., Competing Interests: The authors declare no conflict of interest.

APETALA2/ethylene response factor (AP2/ERF) is widely found in the plant kingdom and plays crucial roles in transcriptional regulation and defense response of plant growth and development. Based on the research progress related to AP2/ERF genes, this paper focuses on the classification and structural features of AP2/ERF transcription factors, reviews the roles of rice AP2/ERF genes in the regulation of growth, development and stress responses, and discusses rice breeding potential and challenges. Taken together; studies of rice AP2/ERF genes may help to elucidate and enrich the multiple molecular mechanisms of how AP2/ERF genes regulate spikelet determinacy and floral organ development, flowering time, grain size and quality, embryogenesis, root development, hormone balance, nutrient use efficiency, and biotic and abiotic response processes. This will contribute to breeding excellent rice varieties with high yield and high resistance in a green, organic manner.

Forkhead box (FOX) proteins are a wing-like helix family of transcription factors in the DNA-binding region. By mediating the activation and inhibition of transcription and interactions with all kinds of transcriptional co-regulators (MuvB complexes, STAT3, β-catenin, etc.), they play significant roles in carbohydrate and fat metabolism, biological aging and immune regulation, development, and diseases in mammals. Recent studies have focused on translating these essential findings into clinical applications in order to improve quality of life, investigating areas such as diabetes, inflammation, and pulmonary fibrosis, and increase human lifespan. Early studies have shown that forkhead box M1 (FOXM1) functions as a key gene in pathological processes in multiple diseases by regulating genes related to proliferation, the cell cycle, migration, and apoptosis and genes related to diagnosis, therapy, and injury repair. Although FOXM1 has long been studied in relation to human diseases, its role needs to be elaborated on. FOXM1 expression is involved in the development or repair of multiple diseases, including pulmonary fibrosis, pneumonia, diabetes, liver injury repair, adrenal lesions, vascular diseases, brain diseases, arthritis, myasthenia gravis, and psoriasis. The complex mechanisms involve multiple signaling pathways, such as WNT/β-catenin, STAT3/FOXM1/GLUT1, c-Myc/FOXM1, FOXM1/SIRT4/NF-κB, and FOXM1/SEMA3C/NRP2/Hedgehog. This paper reviews the key roles and functions of FOXM1 in kidney, vascular, lung, brain, bone, heart, skin, and blood vessel diseases to elucidate the role of FOXM1 in the development and progression of human non-malignant diseases and makes suggestions for further research. [ABSTRACT FROM AUTHOR]

Flavane-3-ol monomers are the precursors of proanthocyanidins (PAs), which play a crucial role in grape resistance. Previous studies showed that UV-C positively regulated leucoanthocyanidin reductase (LAR) enzyme activity to promote the accumulation of total flavane-3-ols in juvenile grape fruit, but its molecular mechanism was still unclear. In this paper, we found that the contents of flavane-3-ol monomers increased dramatically at the early development stage grape fruit after UV-C treatment, and the expression of its related transcription factor VvMYBPA1 was also enhanced significantly. The contents of (−)-epicatechin and (+)-catechin, the expression level of VvLAR1 and VvANR, and the activities of LAR and anthocyanidin reductase (ANR) were improved significantly in the VvMYBPA1 overexpressed grape leaves compared to the empty vector. Both VvMYBPA1 and VvMYC2 could interact with VvWDR1 using bimolecular fluorescence complementation (BiFC) and yeast two hybrid (Y2H). Finally, VvMYBPA1 was proven to bind with the promoters of VvLAR1 and VvANR by yeast one hybrid (Y1H). To sum up, we found that the expression of VvMYBPA1 increased in the young stage of grape fruit after UV-C treatment. VvMYBPA1 formed a trimer complex with VvMYC2 and VvWDR1 to regulate the expression of VvLAR1 and VvANR, thus positively promoting the activities of LAR and ANR enzyme, and eventually improved the accumulation of flavane-3-ols in grape fruit. [ABSTRACT FROM AUTHOR]

The WRKY gene family is one of the most significant transcription factor (TF) families in higher plants and participates in many secondary metabolic processes in plants. Litsea cubeba (Lour.) Person is an important woody oil plant that is high in terpenoids. However, no studies have been conducted to investigate the WRKY TFs that regulate the synthesis of terpene in L. cubeba. This paper provides a comprehensive genomic analysis of the LcWRKYs. In the L. cubeba genome, 64 LcWRKY genes were discovered. According to a comparative phylogenetic study with Arabidopsis thaliana, these L. cubeba WRKYs were divided into three groups. Some LcWRKY genes may have arisen from gene duplication, but the majority of LcWRKY evolution has been driven by segmental duplication events. Based on transcriptome data, a consistent expression pattern of LcWRKY17 and terpene synthase LcTPS42 was found at different stages of L. cubeba fruit development. Furthermore, the function of LcWRKY17 was verified by subcellular localization and transient overexpression, and overexpression of LcWRKY17 promotes monoterpene synthesis. Meanwhile, dual-Luciferase and yeast one-hybrid (Y1H) experiments showed that the LcWRKY17 transcription factor binds to W-box motifs of LcTPS42 and enhances its transcription. In conclusion, this research provided a fundamental framework for future functional analysis of the WRKY gene families, as well as breeding improvement and the regulation of secondary metabolism in L. cubeba. [ABSTRACT FROM AUTHOR]

Keap1 (Kelch-like ECH-associated protein 1) is one of the major negative regulators of the transcription factor Nrf2 (nuclear factor erythroid-2-related factor 2), which induces the expression of numerous proteins defending the cell against different stress conditions. Keap1 is generally negatively regulated by post-translational modification (mostly via its cysteine residues) and interaction with other proteins that compete with Nrf2 for binding. Cysteine residues in Keap1 have different effects on protein regulation, as basic residues (Lys, Arg, and His) in close proximity to them increase cysteine modification potential. In this paper, we present an evolutionary analysis of residues involved in both mechanisms of Keap1 regulation in the broader context of the KLHL protein family in vertebrates. We identified the typical domain structure of the KLHL protein family in several proteins outside of this family (namely in KBTBD proteins 2, 3, 4, 6, 7, 8, 12 and 14). We found several cysteines that are flanked by basic residues (namely, C14, C38, C151, C226, C241, C273, C288, C297, C319, and C613) and, therefore, may be considered more susceptible to regulatory modification. The Nrf2 binding site is completely conserved in Keap1 in vertebrates but is absent or located in nonaligned DA and BC loops of the Kelch domain within the KLHL family. The development of specific substrate binding regions could be an evolutionary factor of diversification in the KLHL protein family. [ABSTRACT FROM AUTHOR]

Transcription factors are an integral component of the cellular machinery responsible for regulating many biological processes, and they recognize distinct DNA sequence patterns as well as internal/external signals to mediate target gene expression. The functional roles of an individual transcription factor can be traced back to the functions of its target genes. While such functional associations can be inferred through the use of binding evidence from high-throughput sequencing technologies available today, including chromatin immunoprecipitation sequencing, such experiments can be resource-consuming. On the other hand, exploratory analysis driven by computational techniques can alleviate this burden by narrowing the search scope, but the results are often deemed low-quality or non-specific by biologists. In this paper, we introduce a data-driven, statistics-based strategy to predict novel functional associations for transcription factors in the model plant Arabidopsis thaliana. To achieve this, we leverage one of the largest available gene expression compendia to build a genome-wide transcriptional regulatory network and infer regulatory relationships among transcription factors and their targets. We then use this network to build a pool of likely downstream targets for each transcription factor and query each target pool for functionally enriched gene ontology terms. The results exhibited sufficient statistical significance to annotate most of the transcription factors in Arabidopsis with highly specific biological processes. We also perform DNA binding motif discovery for transcription factors based on their target pool. We show that the predicted functions and motifs strongly agree with curated databases constructed from experimental evidence. In addition, statistical analysis of the network revealed interesting patterns and connections between network topology and system-level transcriptional regulation properties. We believe that the methods demonstrated in this work can be extended to other species to improve the annotation of transcription factors and understand transcriptional regulation on a system level. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative disorder that results from the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Since there are only symptomatic treatments available, new cellular and molecular targets involved in the onset and progression of this disease are needed to develop effective treatments. CCAAT/Enhancer Binding Protein β (C/EBPβ) transcription factor levels are altered in patients with a variety of neurodegenerative diseases, suggesting that it may be a good therapeutic target for the treatment of PD. A list of genes involved in PD that can be regulated by C/EBPβ was generated by the combination of genetic and in silico data, the mitochondrial transcription factor A (TFAM) being among them. In this paper, we observed that C/EBPβ overexpression increased TFAM promoter activity. However, downregulation of C/EBPβ in different PD/neuroinflammation cellular models produced an increase in TFAM levels, together with other mitochondrial markers. This led us to propose an accumulation of non-functional mitochondria possibly due to the alteration of their autophagic degradation in the absence of C/EBPβ. Then, we concluded that C/EBPβ is not only involved in harmful processes occurring in PD, such as inflammation, but is also implicated in mitochondrial function and autophagy in PD-like conditions. [ABSTRACT FROM AUTHOR]

Background: As a member of the Krüppel-like factor (KLFs) family, Krüppel-like factor 6 (KLF6) plays a critical role in regulating key cellular functions. Presently, scholars have proved the important role of KLF6 in the tumorigenesis of certain cancers through a large number of experiments. However, gaps still remain in our knowledge of the role of KLF6 in pancreatic cancer (PAAD). Therefore, this paper mainly investigates the role of KLF6 in the progression of pancreatic cancer. Methods: The expression pattern of KLF6 in pancreatic cancer was explored in pancreatic cancer tissues and cell lines. Then, we investigated the prognostic value of KLF6 in pancreatic cancer by immunohistochemical assays. Next, Cell Counting Kit-8 (CCK8) and clone information assays were employed to explore the proliferation of PAAD affected by KLF6. The metastasis and epithelial-mesenchymal transition (EMT) abilities affected by KLF6 were identified through transwell invasion as well as migration assays and western blots. Finally, the TRRUST tool was used to analyze the potential targeted genes of KLF6. The results were verified by Quantificational Real-time Polymerase Chain Reaction (qRT-PCR), western blot and rescue assays. Results: KLF6 expresses lowly in pancreatic cancer compared to corresponding normal tissues and relates to poor survival times. Overexpression of KLF6 inhibits the proliferation, metastasis, and EMT progression in pancreatic cancer cells. Further studies suggest that KLF6 could upregulate ATF3 in PAAD. Conclusions: Our results suggest that KLF6 can be a useful factor in predicting the prognosis of PAAD patients and that it inhibits the progression of pancreatic cancer by upregulating activating transcription factor 3 (ATF3). [ABSTRACT FROM AUTHOR]

Unspecific antibody binding takes a significant toll on researchers in the form of both the economic burden and the disappointed hopes of promising new therapeutic targets. Despite recent initiatives promoting antibody validation, a uniform approach addressing this issue has not yet been developed. Here, we demonstrate that the anti-glucocorticoid receptor (GR) antibody clone 5E4 predominantly targets two different proteins of approximately the same size, namely AMP deaminase 2 (AMPD2) and transcription intermediary factor 1-beta (TRIM28). This paper is intended to generate awareness of unspecific binding of well-established reagents and advocate the use of more rigorous verification methods to improve antibody quality in the future.

Transcription factors (TFs) are proteins that control the transcription of a gene from DNA to messenger RNA (mRNA). TFs bind to a specific DNA sequence called a binding site. Transcription factor binding sites have not yet been completely identified, and this is considered to be a challenge that could be approached computationally. This challenge is considered to be a classification problem in machine learning. In this paper, the prediction of transcription factor binding sites of SP1 on human chromosome1 is presented using different classification techniques, and a model using voting is proposed. The highest Area Under the Curve (AUC) achieved is 0.97 using K-Nearest Neighbors (KNN), and 0.95 using the proposed voting technique. However, the proposed voting technique is more efficient with noisy data. This study highlights the applicability of the voting technique for the prediction of binding sites, and highlights the outperformance of KNN on this type of data. The study also highlights the significance of using voting. [ABSTRACT FROM AUTHOR]

Simple Summary: Soldiers and workers collectively perform defensive behaviors in termite colonies. To determine the molecular mechanism driving the defensive behaviors of termite soldiers, we tested the effect of the juvenile hormone analogue pyriproxyfen (JHA) and the soldier caste-specific protein 1 (RaSsp1) on the defensive behaviors of Reticulitermes aculabialis soldiers when encountering an ant invasion. The results showed that JHA-feeding may affect defensive behaviors (i.e., bites and head-banging) of soldiers via downregulation of RaSsp1 expression. Feeding JHA may also affect the content of alarm pheromones in soldiers, including limonene, which also influenced the defensive behavior of soldiers. These results suggest that JH and RaSsp1 may play important roles in modulating social defense in termite colonies. Eusocial insects have evolved specific defensive strategies to protect their colonies. In termite colonies, soldiers perform a colony-level defense by displaying mechanical biting, head-banging and mandible opening–closing behaviors. However, few studies have been reported on the factors modulating defensive behaviors in termites. Owing to JH (juvenile hormone) being involved in soldier differentiation, JH was speculated to affect defensive behaviors in termite soldiers. To determine the effect of JH on the defensive behaviors of termite soldiers, we performed a JHA-feeding and RaSsp1-silencing experiment and then tested the changes in defense-related behaviors, alarm pheromones and key JH signaling genes. The observed result was that after feeding workers with JHA, soldiers displayed the following: (1) decreased biting events and increased head-banging events; (2) a reduced expression of RaSsp1 and increased expression of Met (methoprene-tolerant, the nuclear receptor of JH) and Kr-h1 (the JH-inducible transcription factor Krüppel homolog 1); and (3) a decreased concentration of alarm pheromones, including α-pinene, β-pinene and limonene (+, −). Further study showed that soldiers silenced for RaSsp1 also exhibited (1) decreased biting events and increased head-banging events and (2) increased expression of Met and Kr-h1. In addition, soldiers stimulated by the alarm pheromone limonene displayed an increase in the frequency of mandible opening–closing and biting behavior. All of these results show that JHA influenced the defensive behaviors of termite soldiers, possibly via downregulating RaSsp1 expression, up-regulating Met and Kr-h1 and stimulating the secretion of alarm pheromones, suggesting that the JH pathway plays important roles in modulating social behaviors in termite colonies. [ABSTRACT FROM AUTHOR]

Wax is an acellular structural substance attached to the surface of plant tissues. It forms a protective barrier on the epidermis of plants and plays an important role in resisting abiotic and biotic stresses. In this paper, nonheading Chinese cabbage varieties with and without wax powder were observed using scanning electron microscopy, and the surface of waxy plants was covered with a layer of densely arranged waxy crystals, thus differentiating them from the surface of waxless plants. A genetic analysis showed that wax powder formation in nonheading Chinese cabbage was controlled by a pair of dominant genes. A preliminary bulked segregant analysis sequencing (BSA-seq) assay showed that one gene was located at the end of chromosome A09. Within this interval, we identified BraA09000626, encoding an AP2 transcription factor homologous to Arabidopsis AtSHINE3, and we named it BrSHINE3. By comparing the CDS of the gene in the two parental plants, a 35 bp deletion in the BrSHINE3 gene of waxless plants resulted in a frameshift mutation. Tissue analysis showed that BrSHINE3 was expressed at significantly higher levels in waxy plant rosette stage petioles and bolting stage stems than in the tissues of waxless plants. We speculate that this deletion in BrSHINE3 bases in the waxless material may inhibit wax synthesis. The overexpression of BrSHINE3 in Arabidopsis induced the accumulation of wax on the stem surface, indicating that BrSHINE3 is a key gene that regulates the formation of wax powder in nonheading Chinese cabbage. The analysis of the subcellular localization showed that BrSHINE3 is mainly located in the nucleus and chloroplast of tobacco leaves, suggesting that the gene may function as a transcription factor. Subsequent transcriptome analysis of the homology of BrSHINE3 downstream genes in nonheading Chinese cabbage showed that these genes were downregulated in waxless materials. These findings provide a basis for a better understanding of the nonheading Chinese cabbage epidermal wax synthesis pathway and provide important information for the molecular-assisted breeding of nonheading Chinese cabbage. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) cells contain elevated levels of Stat3 and Smad7, two proteins involved in the growth and survival of neoplastic cells. This study was aimed at examining whether Smad7 positively controls the expression of Stat3 in CRC cells. By employing antisense technology, which specifically inhibits Smad7 expression in selected cells, we hereby show that the reduction of Smad7 in CRC cells is paralleled by the marked suppression of the levels of Stat3 and of Stat3-related genes. Finally, we provide evidence that in human CRC tissue samples, there is a positive correlation between Smad7 expression and Stat3 content. Overall, these findings delineate a novel positive feedback loop that sustains CRC cell behavior and suggest that Smad7 is a target for therapeutic intervention in patients with such a disease. Colorectal cancer (CRC) cells contain elevated levels of active signal transducer and the activator of transcription (Stat)-3, which exerts proliferative and anti-apoptotic effects. Various molecules produced in the CRC tissue can activate Stat3, but the mechanisms that amplify such an activation are yet to be determined. In this paper, we assessed whether Smad7, an inhibitor of Transforiming Growth Factor (TGF)-β1 activity, sustains Stat3 expression/activation in CRC cells. Both Smad7 and phosphorylated (p)/activated-Stat3 were more expressed in the tumoral areas of CRC patients, compared to the normal adjacent colonic mucosa of the same patients, and were co-localized in primary CRC cells and CRC cell lines. The knockdown of Smad7 with a Smad7 antisense oligonucleotide (AS) reduced p-Stat3 in both unstimulated and interleukin (IL)-6- and IL-22-stimulated DLD-1 and HCT116 cells. Consistently, reduced levels of BCL-xL and survivin, two downstream signaling targets of Stat3 activation, were seen in Smad7 AS-treated cells. An analysis of the mechanisms underlying Smad7 AS-induced Stat3 inactivation revealed that Smad7 AS reduced Stat3 RNA and protein expression. A chromatin immunoprecipitation assay showed the direct regulatory effect of Smad7 on the Stat3 promoter. RNA-sequencing data from the Tumor, Normal and Metastatic (TNM) plot database showed a positive correlation between Smad7 and Stat3 in 1450 CRC samples. To our knowledge, this is the first evidence supporting the theory that Smad7 positively regulates Stat3 function in CRC. [ABSTRACT FROM AUTHOR]

Anthocyanins belong to a group of flavonoids, which are the most important flower pigments. Clarifying the potential anthocyanins biosynthesis molecular mechanisms could facilitate artificial manipulation of flower pigmentation in plants. In this paper, we screened a differentially expressed gene, MhTCP4, from the transcriptome data of Malus halliana petals at different development stages and explored its role in anthocyanins biosynthesis. The transcriptome data and qRT-PCR analysis showed that the expression level of MhTCP4 gradually decreased from the flower color fades. Tissue specific expression analysis showed MhTCP4 was expressed in the petal, leaf, and fruit of M. halliana, and was highly expressed in the scarlet petal. Overexpression of MhTCP4 promoted anthocyanins accumulation and increased pigments in infected parts of M. 'Snowdrift' and M. 'Fuji' fruit peels. In contrast, when endogenous MhTCP4 was silenced, the anthocyanins accumulation was inhibited and pigments decreased in the infected peels. The qRT-PCR analysis revealed that overexpression or silence of MhTCP4 caused expression changes of a series of structural genes included in anthocyanins biosynthesis pathway. The yeast two-hybrid assays indicated that MhTCP4 did not interact with MhMYB10. Furthermore, the yeast one-hybrid assays indicated that MhTCP4 did not directly bind to the promoter of MhMYB10, but that of the anthocyanins biosynthesis genes, MhCHI and MhF3′H. Dual luciferase assays further confirmed that MhTCP4 can strongly activate the promoters of MhCHI and MhF3′H in tobacco. Overall, the results suggest that MhTCP4 positively regulates anthocyanins biosynthesis by directly activated MhCHI and MhF3′H in M. halliana flowers. [ABSTRACT FROM AUTHOR]

Regeneration, the restoration of body parts after injury, is quite widespread in the animal kingdom. Species from virtually all Phyla possess regenerative abilities. Human beings, however, are poor regenerators. Yet, the progress of knowledge and technology in the fields of bioengineering, stem cells, and regenerative biology have fostered major advancements in regenerative medical treatments, which aim to regenerate tissues and organs and restore function. Human induced pluripotent stem cells can differentiate into any cell type of the body; however, the structural and cellular complexity of the human tissues, together with the inability of our adult body to control pluripotency, require a better mechanistic understanding. Planarians, with their capacity to regenerate lost body parts thanks to the presence of adult pluripotent stem cells could help providing such an understanding. In this paper, we used a top-down approach to shortlist blastema transcription factors (TFs) active during anterior regeneration. We found 44 TFs-31 of which are novel in planarian-that are expressed in the regenerating blastema. We analyzed the function of half of them and found that they play a role in the regeneration of anterior structures, like the anterior organizer, the positional instruction muscle cells, the brain, the photoreceptor, the intestine. Our findings revealed a glimpse of the complexity of the transcriptional network governing anterior regeneration in planarians, confirming that this animal model is the perfect playground to study in vivo how pluripotency copes with adulthood.

Simple Summary: Given the importance of the epithelial-to-mesenchymal transition in tumor progression and the pivotal role of ZEB1 as a transcriptional repressor during this process, the regulation of ZEB1-targeted gene expression is an active area of investigation. Diverse signaling pathways converge to induce ZEB1 activity, but few studies have focused on the enzyme-dependent modifications of ZEB1 that occur after its translation from mRNA (i.e., post-translational modifications, PTM). In addition to outlining the current knowledge in the field, we outline several questions regarding the PTM-mediated regulation of ZEB1 that remain unanswered. Thus, the areas of research covered in this review paper will provide a noteworthy conceptual advancement in our understanding of ZEB1′s biological function, as well as its post-transcriptional and post-translational regulation. Furthermore, the review will enhance the development of treatment strategies by identifying knowledge gaps in ZEB1′s regulatory mechanisms that could potentially be targeted to prevent and treat metastasis in cancer patients. Zinc finger E-box binding homeobox 1 (ZEB1) is a pleiotropic transcription factor frequently expressed in carcinomas. ZEB1 orchestrates the transcription of genes in the control of several key developmental processes and tumor metastasis via the epithelial-to-mesenchymal transition (EMT). The biological function of ZEB1 is regulated through pathways that influence its transcription and post-transcriptional mechanisms. Diverse signaling pathways converge to induce ZEB1 activity; however, only a few studies have focused on the molecular associations or functional changes of ZEB1 by post-translational modifications (PTMs). Due to the robust effect of ZEB1 as a transcription repressor of epithelial genes during EMT, the contribution of PTMs in the regulation of ZEB1-targeted gene expression is an active area of investigation. Herein, we review the pivotal roles that phosphorylation, acetylation, ubiquitination, sumoylation, and other modifications have in regulating the molecular associations and behavior of ZEB1. We also outline several questions regarding the PTM-mediated regulation of ZEB1 that remain unanswered. The areas of research covered in this review are contributing to new treatment strategies for cancer by improving our mechanistic understanding of ZEB1-mediated EMT. [ABSTRACT FROM AUTHOR]

The transcription factor WRKY is widely distributed in the plant kingdom, playing a significant role in plant growth, development and response to stresses. Walnut is an economically important temperate tree species valued for both its edible nuts and high-quality wood, and its response to various stresses is an important factor that determines the quality of its fruit. However, in walnut trees themselves, information about the WRKY gene family remains scarce. In this paper, we perform a comprehensive study of the WRKY gene family in walnut. In total, we identified 103 WRKY genes in the common walnut that are clustered into 4 groups and distributed on 14 chromosomes. The conserved domains all contained a WRKY domain, and motif 2 was observed in most WRKYs , suggesting a high degree of conservation and similar functions within each subfamily. However, gene structure was significantly differentiated between different subfamilies. Synteny analysis indicates that there were 56 gene pairs in J. regia and A. thaliana , 76 in J. regia and J. mandshurica , 75 in J. regia and J. microcarpa , 76 in J. regia and P. trichocarpa , and 33 in J. regia and Q. robur , indicating that the WRKY gene family may come from a common ancestor. GO and KEGG enrichment analysis showed that the WRKY gene family was involved in resistance traits and the plant-pathogen interaction pathway. In anthracnose-resistant F26 fruits (AR) and anthracnose-susceptible F423 fruits (AS), transcriptome and qPCR analysis results showed that JrWRKY83 , JrWRKY73 and JrWRKY74 were expressed significantly more highly in resistant cultivars, indicating that these three genes may be important contributors to stress resistance in walnut trees. Furthermore, we investigate how these three genes potentially target miRNAs and interact with proteins. JrWRKY73 was target by the miR156 family, including 12 miRNAs; this miRNA family targets WRKY genes to enhance plant defense. JrWRKY73 also interacted with the resistance gene AtMPK6 , showing that it may play a crucial role in walnut defense.

Predicting in vivo protein-DNA binding sites is a challenging but pressing task in a variety of fields like drug design and development. Most promoters contain a number of transcription factor (TF) binding sites, but only a small minority has been identified by biochemical experiments that are time-consuming and laborious. To tackle this challenge, many computational methods have been proposed to predict TF binding sites from DNA sequence. Although previous methods have achieved remarkable performance in the prediction of protein-DNA interactions, there is still considerable room for improvement. In this paper, we present a hybrid deep learning framework, termed DeepD2V, for transcription factor binding sites prediction. First, we construct the input matrix with an original DNA sequence and its three kinds of variant sequences, including its inverse, complementary, and complementary inverse sequence. A sliding window of size k with a specific stride is used to obtain its k -mer representation of input sequences. Next, we use word2vec to obtain a pre-trained k -mer word distributed representation model. Finally, the probability of protein-DNA binding is predicted by using the recurrent and convolutional neural network. The experiment results on 50 public ChIP-seq benchmark datasets demonstrate the superior performance and robustness of DeepD2V. Moreover, we verify that the performance of DeepD2V using word2vec-based k -mer distributed representation is better than one-hot encoding, and the integrated framework of both convolutional neural network (CNN) and bidirectional LSTM (bi-LSTM) outperforms CNN or the bi-LSTM model when used alone. The source code of DeepD2V is available at the github repository.

Synonymous variants, traditionally regarded as silent mutations due to their lack of impact on protein sequence, structure and function, have been the subject of increasing scrutiny. This commentary explores the emerging evidence challenging the notion of synonymous variants as functionally inert. Analysis of the activity of 70 synonymous variants in the HIV Tat transcription factor revealed that 50% of the variants exhibited significant deviations from wild-type activity. Our analysis supports previous work and raises important questions about the broader impact of non-silent synonymous variants in human genes. Considering the potential functional implications, the authors propose classifying such variants as "synonymous variants of uncertain silence" (sVUS), highlighting the need for cautious interpretation and further investigations in clinical and genetic testing settings. [ABSTRACT FROM AUTHOR]