Member Of Transcription Factor Family Research Articles

Genome-Wide Identification of NAC Gene Family Members of Tree Peony (Paeonia suffruticosa Andrews) and Their Expression under Heat and Waterlogging Stress.

An important family of transcription factors (TFs) in plants known as NAC (NAM, ATAF1/2, and CUC2) is crucial for the responses of plants to environmental stressors. In this study, we mined the NAC TF family members of tree peony (Paeonia suffruticosa Andrews) from genome-wide data and analyzed their response to heat and waterlogging stresses in conjunction with transcriptome data. Based on tree peony's genomic information, a total of 48 PsNAC genes were discovered. Based on how similar their protein sequences were, these PsNAC genes were divided into 14 branches. While the gene structures and conserved protein motifs of the PsNAC genes within each branch were largely the same, the cis-acting elements in the promoter region varied significantly. Transcriptome data revealed the presence of five PsNAC genes (PsNAC06, PsNAC23, PsNAC38, PsNAC41, PsNAC47) and one PsNAC gene (PsNAC37) in response to heat and waterlogging stresses, respectively. qRT-PCR analysis reconfirmed the response of these five PsNAC genes to heat stress and one PsNAC gene to waterlogging stress. This study lays a foundation for the study of the functions and regulatory mechanisms of NAC TFs in tree peony. Meanwhile, the NAC TFs of tree peony in response to heat and waterlogging stress were excavated, which is of great significance for the selection and breeding of new tree peony varieties with strong heat and waterlogging tolerance.

Transcriptome-Based Screening of Candidate Low-Temperature-Associated Genes and Analysis of the BocARR-B Transcription Factor Gene Family in Kohlrabi (Brassica oleracea L. var. caulorapa L.).

Low temperature is a significant abiotic stress factor that not only impacts plant growth, development, yield, and quality but also constrains the geographical distribution of numerous wild plants. Kohlrabi (Brassica oleracea L. var. caulorapa L.) belongs to the Brassicaceae family and has a short growing period. In this study, a total of 196,642 unigenes were obtained from kohlrabi seedlings at low temperatures; of these, 52,836 unigenes were identified as differentially expressed genes. Transcription factor family members ARR-B, C3H, B3-ARF, etc. that had a high correlation with biochemical indicators related to low temperature were identified. A total of nineteen BocARR-B genes (named BocARR-B1-BocARR-B19) were obtained, and these genes were distributed unevenly across seven chromosomes. Nineteen BocARR-B genes searched four conserved motifs and were divided into three groups. The relative expression level analysis of 19 BocARR-B genes of kohlrabi showed obvious specificity in different tissues. This study lays a foundation and provides new insight to explain the low-temperature resistance mechanism and response pathways of kohlrabi. It also provides a theoretical basis for the functional analysis of 19 BocARR-B transcription factor gene family members.

Genome-wide identification, phylogeny and expression analysis of Hsf gene family in Verbena bonariensis under low-temperature stress

BackgroundThe heat shock transcription factor (Hsf) is a crucial regulator of plant stress resistance, playing a key role in plant stress response, growth, and development regulation.ResultsIn this study, we utilized bioinformatics tools to screen 25 VbHsf members, which were named VbHsf1-VbHsf25. We used bioinformatics methods to analyze the sequence structure, physicochemical properties, conserved motifs, phylogenetic evolution, chromosome localization, promoter cis-acting elements, collinearity, and gene expression of Hsf heat shock transcription factor family members under low-temperature stress. The results revealed that the majority of the Hsf genes contained motif1, motif2, and motif3, signifying that these three motifs were highly conserved in the Hsf protein sequence of Verbena bonariensis. Although there were some variations in motif deletion among the members, the domain remained highly conserved. The theoretical isoelectric point ranged from 4.17 to 9.71, with 21 members being unstable proteins and the remainder being stable proteins. Subcellular localization predictions indicated that all members were located in the nucleus. Phylogenetic analysis of the Hsf gene family in V. bonariensis and Arabidopsis thaliana revealed that the Hsf gene family of V. bonariensis could be categorized into three groups, with group A comprising 17 members and group C having at least two members. Among the 25 Hsf members, there were 1–3 exons located on seven chromosome fragments, which were unevenly distributed. Collinearity analysis demonstrated the presence of seven pairs of homologous genes in the VbHsf gene family. The Ka/Ks ratios were less than one, indicating that the VbHsf gene underwent purification selection pressure. Additionally, nine genes in V. bonariensis were found to have collinearity with A. thaliana. Promoter analysis revealed that the promoters of all VbHsf genes contained various types of cis-acting elements related to hormones and stress. Based on RNA-seq data, qRT-PCR analysis of six highly expressed genes was performed, and it was found that VbHsf5, VbHsf14, VbHsf17, VbHsf18, VbHsf20 and VbHsf21 genes were highly expressed at 12 h of low-temperature treatment, and the expression decreased after 24 h, among which VbHsf14 was up-regulated at 12 h of low-temperature by 70-fold.ConclusionsOur study may help reveal the important roles of Hsf in plant development and show insight for the further molecular breeding of V. bonariensis.

WNT inhibitory factor 1 (WIF1) is a novel fusion partner of RUNX family transcription factor 1 (RUNX1) in acute myeloid leukemia with t(12;21)(q14;q22).

As a member of the core transcription factor family, RUNX1 plays an important role in stem cell differentiation. RUNX1 rearrangements are common in myeloid and lymphoid tumors [1]. (Blood 129(15):2070-2082, 2017). One of the most commonly detected abnormalities in acute myeloid leukemia (AML) is the translocation t(8;21)(q22;q22) (Blood Adv 4(1):229-238, 2020), resulting in a RUNX1::RUNX1T1 fusion. Occasionally, RUNX1 is translocated with other genes. This article describes an AML patient with a specific chromosomal translocation involving the RUNX1 gene and the identification of the RUNX1::WIF1 fusion. Chromosomal abnormalities were detected through karyotype analysis, break gene involved was identified via fluorescence in situ hybridization (FISH), and the novel fusion was identified through transcriptome sequencing and subsequently confirmed through reverse transcription-polymerase chain reaction (RT-PCR) and Sanger sequencing. A 79-year-old female patient diagnosed with AML was found to have a t(12;21)(q14;q12) translocation. FISH analysis provided evidence of RUNX1 gene rearrangement. Additionally, transcriptomic sequencing revealed a novel fusion known as RUNX1::WIF1, which consists of RUNX1 exon 2 and WIF1 exon 3. The novel fusion was further confirmed through RT-PCR and Sanger sequencing. We identified WIF1 as a novel fusion partner of RUNX1 in AML. Additionally, this is the first report of a RUNX1 fusion gene with the break point in intron 2, resulting in an out-of-frame fusion. Further research is needed to investigate the impact of this novel fusion on the establishment and progression of the disease.

Intervention of epithelial mesenchymal transition against colon cancer cell growth and metastasis based on SOX21/POU4F2/Hedgehog signaling axis

AimsColon cancer poses a major threat to human health and a heavy burden on the national economy. As a member of the SOX transcription factor family, SRY-box transcription factor 21 (SOX21) is associated with various cancers, but its mechanism of action in colon cancer remains unclear. This study focused on the molecular mechanisms of transcription factor SOX21 in proliferation and metastasis of colon cancer cells. Main methodsWe analyzed SOX21 expression level and its impact on survival in colon cancer patients by bioinformatics analysis. We used public databases for gene correlation, GSEA enrichment analysis. Cell function experiments (colony formation assay, wound healing assay, Transwell migration and invasion assay) were utilized to determine the impact of SOX21 silencing and over-expression on cell proliferation and metastasis. The luciferase reporter assay, CUT&RUN-qPCR assay and Methylation Specific PCR were used to explore SOX21-POU class 4 homeobox 2 (POU4F2) molecular interactions. The molecular mechanisms were verified by Quantitative real-time PCR and Western blot analysis. Key findingsSOX21 is highly expressed and affects the overall survival of colon cancer patients. SOX21 can attenuates POU4F2 methylation state by binding with it. In addition, this interaction facilitate its transcriptional activation of Hedgehog pathway, mediates epithelial-mesenchymal transition (EMT), consequently promoting the proliferation and metastasis of colon cancer cells. SignificanceOur study reveals that SOX21 is an oncogenic molecule and suggests its regulatory role in colon carcinogenesis and progression, providing new insights into the treatment of this disease.

Forkhead box O1 in metabolic dysfunction-associated fatty liver disease: molecular mechanisms and drug research.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a chronic liver disease that progresses from hepatic steatosis to non-alcoholic steatohepatitis, cirrhosis, and liver cancer, posing a huge burden on human health. Existing research has confirmed that forkhead box O1 (FOXO1), as a member of the FOXO transcription factor family, is upregulated in MAFLD. Its activity is closely related to nuclear-cytoplasmic shuttling and various post-translational modifications including phosphorylation, acetylation, and methylation. FOXO1 mediates the progression of MAFLD by regulating glucose metabolism, lipid metabolism, insulin resistance, oxidative stress, hepatic fibrosis, hepatocyte autophagy, apoptosis, and immune inflammation. This article elaborates on the regulatory role of FOXO1 in MAFLD, providing a summary and new insights for the current status of drug research and targeted therapies for MAFLD.

TFAP2A downregulation mediates tumor-suppressive effect of miR-8072 in triple-negative breast cancer via inhibiting SNAI1 transcription

BackgroundTriple-negative breast cancer (TNBC) represents a highly aggressive subset of breast malignancies characterized by its challenging clinical management and unfavorable prognosis. While TFAP2A, a member of the AP-2 transcription factor family, has been implicated in maintaining the basal phenotype of breast cancer, its precise regulatory role in TNBC remains undefined.MethodsIn vitro assessments of TNBC cell growth and migratory potential were conducted using MTS, colony formation, and EdU assays. Quantitative PCR was employed to analyze mRNA expression levels, while Western blot was utilized to evaluate protein expression and phosphorylation status of AKT and ERK. The post-transcriptional regulation of TFAP2A by miR-8072 and the transcriptional activation of SNAI1 by TFAP2A were investigated through luciferase reporter assays. A xenograft mouse model was employed to assess the in vivo growth capacity of TNBC cells.ResultsSelective silencing of TFAP2A significantly impeded the proliferation and migration of TNBC cells, with elevated TFAP2A expression observed in breast cancer tissues. Notably, TNBC patients exhibiting heightened TFAP2A levels experienced abbreviated overall survival. Mechanistically, TFAP2A was identified as a transcriptional activator of SNAI1, a crucial regulator of epithelial-mesenchymal transition (EMT) and cellular proliferation, thereby augmenting the oncogenic properties of TFAP2A in TNBC. Moreover, miR-8072 was unveiled as a negative regulator of TFAP2A, exerting potent inhibitory effects on TNBC cell growth and migration. Importantly, the tumor-suppressive actions mediated by the miR-8072/TFAP2A axis were intricately associated with the attenuation of AKT/ERK signaling cascades and the blockade of EMT processes.ConclusionsOur findings unravel the role and underlying molecular mechanism of TFAP2A in driving tumorigenesis of TNBC. Targeting the TFAP2A/SNAI1 pathway and utilizing miR-8072 as a suppressor represent promising therapeutic strategies for treating TNBC.

Transcription factor OsNF-YC1 regulates grain size by coordinating the transcriptional activation of OsMADS1 in Oryza sativa L.

Grain weight, grain number per panicle, and the number of panicles are the three factors that determine rice (Oryza sativa L.) yield. Of these, grain weight, which not only directly determines rice yield but also influences appearance and quality, is often considered the most important for rice production. Here, we describe OsNF-YC1, a member of the NF-Y transcription factor family that regulates rice grain size. OsNF-YC1 knockout plants (osnf-yc1), obtained using CRISPR-Cas9 technology, showed reduced grain weight due to reduced width and thickness, with no change in grain length, leading to a slenderer grain shape. Downregulation of OsNF-YC1 using RNA interference resulted in similar grain phenotypes as osnf-yc1. OsNF-YC1 affects grain formation by regulating both cell proliferation and cell expansion. OsNF-YC1 localizes in both the nucleus and cytoplasm, has transcriptional activation activity at both the N-terminus and C-terminus, and is highly expressed in young panicles. OsNF-YC1 interacts with OsMADS1 both in vivo and in vitro. Further analysis showed that the histone-like structural CBFD-NFYB-HMF domain of OsNF-YC1 conserved in the OsNF-YC transcription factor family can directly interact with the MADS-box domain of OsMADS1 to enhance its transcriptional activation activity. This interaction positively regulates the expression of OsMADS55, the direct downstream target of OsMADS1. Therefore, this paper reveals a potential grain size regulation pathway controlled by an OsNF-YC1-OsMADS1-OsMADS55 module in rice.

Expression of Forkhead Box M1 and Anticancer Effects of FOXM1 Inhibition in Epithelioid Sarcoma

Epithelioid sarcoma (ES) is a rare aggressive sarcoma that, unlike most soft-tissue sarcomas, shows a tendency toward local recurrence and lymph node metastasis. Novel antitumor agents are needed for ES patients. Forkhead box transcription factor 1 (FOXM1) is a member of the Forkhead transcription factor family and is associated with multiple oncogenic functions; FOXM1 is known to be overexpressed and correlated with pathogenesis in various malignancies. In this study, we immunohistochemically analyzed FOXM1 expression levels and their clinical, clinicopathologic, and prognostic significance in 38 ES specimens. In addition, to investigate potential correlations between FOXM1 downregulation and oncologic characteristics, we treated ES cell lines with thiostrepton, a naturally occurring antibiotic that inhibits both small interfering RNA (siRNA) and FOXM1. In the analyses using ES samples, all 38 specimens were diagnosed as positive for FOXM1 by immunohistochemistry. We separated specimens into high (n = 19) and low (n = 19) FOXM1–protein expression groups by staining index score, and into large (n = 12), small (n = 25), and unknown (n = 1) tumor-size groups using a cutoff of 5 cm maximum diameter. Although there were significantly more samples with high FOXM1 expression in the large tumor group (P = .013), there were no significant differences with respect to age (P = 1.00), gender (P = .51), primary site of origin (P = .74), histologic subtypes (P = 1.00), depth (P = .74), or survival rate (P = .288) between the high and low FOXM1–protein expression groups. In the in vitro experiments using ES cell lines, FOXM1 siRNA and thiostrepton successfully downregulated FOXM1 mRNA and protein expression. Furthermore, downregulation of FOXM1 inhibited cell proliferation, drug resistance against chemotherapeutic agents, migration, and invasion and caused cell cycle arrest in the ES cell lines. Finally, cDNA microarray analysis data showed that FOXM1 regulated cIAP2, which is one of the apoptosis inhibitors activated by the TNFα-mediated NF-κB pathway. In conclusion, the FOXM1 gene may be a promising therapeutic target for ES.

ETV5 promotes lupus pathogenesis and follicular helper T cell differentiation by inducing osteopontin expression

Follicular helper T (TFH) cells mediate germinal center reactions to generate high affinity antibodies against specific pathogens, and their excessive production is associated with the pathogenesis of systemic autoimmune diseases such as systemic lupus erythematosus (SLE). ETV5, a member of the ETS transcription factor family, promotes TFH cell differentiation in mice. In this study, we examined the role of ETV5 in the pathogenesis of lupus in mice and humans. T cell-specific deletion of Etv5 alleles ameliorated TFH cell differentiation and autoimmune phenotypes in lupus mouse models. Further, we identified SPP1 as an ETV5 target that promotes TFH cell differentiation in both mice and humans. Notably, extracellular osteopontin (OPN) encoded by SPP1 enhances TFH cell differentiation by activating the CD44-AKT signaling pathway. Furthermore, ETV5 and SPP1 levels were increased in CD4+ T cells from patients with SLE and were positively correlated with disease activity. Taken together, our findings demonstrate that ETV5 is a lupus-promoting transcription factor, and secreted OPN promotes TFH cell differentiation.

MIKC type MADS-box transcription factor LcSVP2 is involved in dormancy regulation of the terminal buds in evergreen perennial litchi (Litchi chinensis Sonn.).

SHORT VEGETATIVE PHASE (SVP), a member of the MADS-box transcription factor family, has been reported to regulate bud dormancy in deciduous perennial plants. Previously, three LcSVPs (LcSVP1, LcSVP2 and LcSVP3) were identified from litchi genome, and LcSVP2 was highly expressed in the terminal buds of litchi during growth cessation or dormancy stages and down-regulated during growth stages. In this study, the role of LcSVP2 in governing litchi bud dormancy was examined. LcSVP2 was highly expressed in the shoots, especially in the terminal buds at growth cessation stage, whereas low expression was showed in roots, female flowers and seeds. LcSVP2 was found to be located in the nucleus and have transcription inhibitory activity. Overexpression of LcSVP2 in Arabidopsis thaliana resulted in a later flowering phenotype compared to the wild-type control. Silencing LcSVP2 in growing litchi terminal buds delayed re-entry of dormancy, resulting in significantly lower dormancy rate. The treatment also significantly up-regulated litchi FLOWERING LOCUS T2 (LcFT2). Further study indicates that LcSVP2 interacts with an AP2-type transcription factor, SMALL ORGAN SIZE1 (LcSMOS1). Silencing LcSMOS1 promoted budbreak and delayed bud dormancy. Abscisic acid (200mg/L), which enforced bud dormancy, induced a short-term increase in the expression of LcSVP2 and LcSMOS1. Our study reveals that LcSVP2 may play a crucial role, likely together with LcSMOS1, in dormancy onset of the terminal bud and may also serve as a flowering repressor in evergreen perennial litchi.

Expression pattern of Runt-related transcription factor (RUNX) family members and the role of RUNX1 during kidney development

Runt-related transcription factor (RUNX) family members play critical roles in the development of multiple organs. Mammalian RUNX family members, consisting of RUNX1, RUNX2, and RUNX3, have distinct tissue-specific expression and function. In this study, we examined the spatiotemporal expression patterns of RUNX family members in developing kidneys and analyzed the role of RUNX1 during kidney development. In the developing mouse kidney, RUNX1 protein was strongly expressed in the ureteric bud (UB) tip and weakly expressed in the distal segment of the renal vesicle (RV), comma-shaped body (CSB), and S-shaped body (SSB). In contrast, RUNX2 protein was restricted to the stroma, and RUNX3 protein was only expressed in immune cells. We also analyzed the expression of RUNX family members in the cynomolgus monkey kidney. We found that expression patterns of RUNX2 and RUNX3 were conserved between rodents and primates, whereas RUNX1 was only expressed in the UB tip, not in the RV, CSB, or SSB of cynomolgus monkeys, suggesting a species differences. We further evaluated the roles of RUNX1 using two different conditional knockout mice: Runx1f/f:HoxB7-Cre and Runx1f/f:R26-CreERT2 and found no abnormalities in the kidney. Our findings showed that RUNX1, which is mainly expressed in the UB tip, is not essential for kidney development.

Metabolic and Transcriptomic Profile Revealing the Differential Accumulating Mechanism in Different Parts of Dendrobium nobile.

Dendrobium nobile is an important orchid plant that has been used as a traditional herb for many years. For the further pharmaceutical development of this resource, a combined transcriptome and metabolome analysis was performed in different parts of D. nobile. First, saccharides, organic acids, amino acids and their derivatives, and alkaloids were the main substances identified in D. nobile. Amino acids and their derivatives and flavonoids accumulated strongly in flowers; saccharides and phenols accumulated strongly in flowers and fruits; alkaloids accumulated strongly in leaves and flowers; and a nucleotide and its derivatives and organic acids accumulated strongly in leaves, flowers, and fruits. Simultaneously, genes for lipid metabolism, terpenoid biosynthesis, and alkaloid biosynthesis were highly expressed in the flowers; genes for phenylpropanoids biosynthesis and flavonoid biosynthesis were highly expressed in the roots; and genes for other metabolisms were highly expressed in the leaves. Furthermore, different members of metabolic enzyme families like cytochrome P450 and 4-coumarate-coA ligase showed differential effects on tissue-specific metabolic accumulation. Members of transcription factor families like AP2-EREBP, bHLH, NAC, MADS, and MYB participated widely in differential accumulation. ATP-binding cassette transporters and some other transporters also showed positive effects on tissue-specific metabolic accumulation. These results systematically elucidated the molecular mechanism of differential accumulation in different parts of D. nobile and enriched the library of specialized metabolic products and promising candidate genes.

Genome-wide identification of the walnut MYC gene family and functional characterization of Xinjiang wild walnut under low-temperature stress.

Introduction: MYC transcription factors are the basic regulators of the jasmonic acid signaling pathway and play important roles in plant growth and development and the response to adverse stress. In recent years, severe winter freezing and late spring frost in the main planting area of walnut in Xinjiang have affected the growth and development of walnut, which has become a prominent problem restricting walnut production. Xinjiang wild walnut is the only remaining wild species of walnuts in China, which contains a lot of genes with excellent traits, and is important for the cultivation and breeding. Methods: In this paper, the physicochemical properties and bioinformatics of MYC transcription factor members in walnut were analyzed, and the nine MYC were screened from the transcriptome data under low temperature stress. At last, we study the subcellular localizations and the expression patterns of the nine MYC members in Xinjiang wild walnut. Results: The results revealed that 30 MYC members were identified from published walnut whole-genome data, and their evolutionary relationships with Arabidopsis and poplar were divided into six groups according to clustering analysis, among which JrMYC22 and JrMYC23 had high homology with PtrMYC2b, which is induced by jasmonic acid in response to low-temperature stress. Walnut MYC members are unevenly distributed on 12 chromosomes. The prediction of promoter cis-acting elements of walnut MYC transcription factor family members revealed that cis-acting elements related to jasmonic acid and lowtemperature stress were the ones with the greatest number of members, with 12. In addition, all nine MYC family members in Xinjiang wild walnut plants responding to low-temperature stress exhibited strong fluorescence responses in the nucleus. The expression levels of these members in response to low-temperature stress revealed that JrMYC28, JrMYC31, JrMYC33, JrMYC34, and JrMYC35 were highly expressed, and it was hypothesized that JrMYC28, JrMYC31, JrMYC33, JrMYC34, and JrMYC35 might play a key role in the response to lowtemperature stress. Discussion: The results of this study provide a theoretical basis for further research on the functional mechanisms of the MYC transcription factor family members in walnut.

Recovery of synaptic loss and depressive-like behavior induced by GATA1 through blocking of the neuroinflammatory response.

GATA1, a member of the GATA transcription factor family, is a critical factor in hematopoietic system development. In a previous study, we demonstrated the increased expression of GATA1 in the dorsolateral prefrontal cortex (dlPFC) of patients suffering from depression and described its role as a transcriptional repressor of synapse-related genes. In this study, we investigated how GATA1 globally altered gene expression using multi-omics approaches. Through the combined analyses of ChIPseq, mRNAseq, and small RNAseq, we profiled genes that are potentially affected by GATA1 in cultured cortical neurons, and Gene Ontology (GO) analysis revealed that GATA1 might be associated with immune-related functions. We hypothesized that GATA1 induces immune activation, which has detrimental effects including synapse loss and depressive-like behavior. To test this hypothesis, we first performed a microglial morphometric analysis of a brain having overexpression of GATA1 because microglia are the resident immune cells of the central nervous system. Fractal analysis showed that the ramification and process length of microglia decreased in brains having GATA1 overexpression compared to the control, suggesting that GATA1 overexpression increases the activation of microglia. Through flow cytometry and immunohistochemical analysis, we found that activated microglia showed pro-inflammatory phenotypes characterized by the expression of CD86 and CD68. Finally, we demonstrated that the effects of GATA1 overexpression including synapse loss and depressive-like behavior could be blocked by inhibiting microglial activation using minocycline. These results will elucidate the regulatory mechanisms of GATA1 that affect pathophysiological conditions such as depression and provide a potential target for the treatment of depression.

Transcription factor EHF drives cholangiocarcinoma development through transcriptional activation of glioma-associated oncogene homolog 1 and chemokine CCL2.

Cholangiocarcinoma (CCA) is characterized by rapid onset and high chance of metastasis. Therefore, identification of novel therapeutic targets is imperative. E26 transformation-specific homologous factor (EHF), a member of the E26 transformation-specific transcription factor family, plays a pivotal role in epithelial cell differentiation and cancer progression. However, its precise role in CCA remains unclear. In this study, through in vitro and in vivo experiments, we demonstrated that EHF plays a profound role in promoting CCA by transcriptional activation of glioma-associated oncogene homolog 1 (GLI1). Moreover, EHF significantly recruited and activated tumor-associated macrophages (TAMs) through the C-C motif chemokine 2/C-C chemokine receptor type 2 (CCL2/CCR2) axis, thereby remodeling the tumor microenvironment. In human CCA tissues, EHF expression was positively correlated with GLI1 and CCL2 expression, and patients with co-expression of EHF/GLI1 or EHF/CCL2 had the most adverse prognosis. Furthermore, the combination of the GLI1 inhibitor, GANT58, and CCR2 inhibitor, INCB3344, substantially reduced the occurrence of EHF-mediated CCA. In summary, our findings suggest that EHF is a potential prognostic biomarker for patients with CCA, while also advocating the therapeutic approach of combined targeting of GLI1 and CCL2/CCR2-TAMs to inhibit EHF-driven CCA development.

The key pathways for drought tolerance in Cerasus humilis were unveiled through transcriptome analysis.

Drought stress exerts a significant impact on the growth, development, and yield of fruit trees. Cerasus humilis is an endemic drought-resistant fruit tree in northern China. To elucidate the underlying mechanism of drought resistance in C. humilis, comprehensive physiological measurements and transcriptome analysis were conducted on the leaves of C. humilis subjected to 15- or 22-days of drought stress. We identified multiple GO terms and KEGG pathways associated with the drought stress response by performing GO and KEGG analysis on DEGs. Furthermore, through the prediction of transcription factors (TFs) and analysis of their expression levels, we observed differential expression patterns among most members of stress-responsive TF families as the duration of drought stress increased. WGCNA analysis was performed on the transcriptome to identify gene cluster modules that exhibited a strong correlation with the durations of drought. Subsequently, these modules underwent GO and KEGG enrichment analyses. The study revealed that the TF-mediated lignin biosynthesis pathway, along with the plant hormone signal transduction pathway, played a prominent role in responding to drought stress of C. humilis. Gene profiling analysis, qRT-PCR, and determination of phytohormone and lignin contents further supported this hypothesis. The hierarchical gene regulatory network was finally constructed based on DEGs from the aforementioned key enriched pathways to predict the gene regulatory mechanisms in response to stress for C. humilis. The findings from this study provide valuable insights into how C. humilis copes with drought stress while analyzing crucial gene pathways associated with its resistance from a TF perspective. This research is significant for the genetic breeding of economic forests.

Liver cancer development driven by the AP-1/c-Jun~Fra-2 dimer through c-Myc

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. HCC incidence is on the rise, while treatment options remain limited. Thus, a better understanding of the molecular pathways involved in HCC development has become a priority to guide future therapies. While previous studies implicated the Activator Protein-1 (AP-1) (Fos/Jun) transcription factor family members c-Fos and c-Jun in HCC formation, the contribution of Fos-related antigens (Fra-) 1 and 2 is unknown. Here, we show that hepatocyte-restricted expression of a single chain c-Jun~Fra-2 protein, which functionally mimics the c-Jun/Fra-2 AP-1 dimer, results in spontaneous HCC formation in c-Jun~Fra-2hep mice. Several hallmarks of human HCC, such as cell cycle dysregulation and the expression of HCC markers are observed in liver tumors arising in c-Jun~Fra-2hep mice. Tumorigenesis occurs in the context of mild inflammation, low-grade fibrosis, and Pparγ-driven dyslipidemia. Subsequent analyses revealed increased expression of c-Myc, evidently under direct regulation by AP-1 through a conserved distal 3' enhancer. Importantly, c-Jun~Fra-2-induced tumors revert upon switching off transgene expression, suggesting oncogene addiction to the c-Jun~Fra-2 transgene. Tumors escaping reversion maintained c-Myc and c-Myc target gene expression, likely due to increased c-Fos. Interfering with c-Myc in established tumors using the Bromodomain and Extra-Terminal motif inhibitor JQ-1 diminished liver tumor growth in c-Jun~Fra-2 mutant mice. Thus, our data establish c-Jun~Fra-2hep mice as a model to study liver tumorigenesis and identify the c-Jun/Fra-2-Myc interaction as a potential target to improve HCC patient stratification and/or therapy.

Differentially Expressed Genes Identification of Kohlrabi Seedlings (Brassica oleracea var. caulorapa L.) under Polyethylene Glycol Osmotic Stress and AP2/ERF Transcription Factor Family Analysis.

Osmotic stress is a condition in which plants do not get enough water due to changes in environmental factors. Plant response to osmotic stress is a complex process involving the interaction of different stress-sensitive mechanisms. Differentially expressed genes and response mechanisms of kohlrabi have not been reported under osmotic stress. A total of 196,642 unigenes and 33,040 differentially expressed unigenes were identified in kohlrabi seedlings under polyethylene glycol osmotic stress. AP2/ERF, NAC and eight other transcription factor family members with a high degree of interaction with CAT and SOD antioxidant enzyme activity were identified. Subsequently, 151 AP2/ERF genes were identified and analyzed. Twelve conserved motifs were searched and all AP2/ERF genes were clustered into four groups. A total of 149 AP2/ERF genes were randomly distributed on the chromosome, and relative expression level analysis showed that BocAP2/ERF genes of kohlrabi have obvious specificity in different tissues. This study lays a foundation for explaining the osmotic stress resistance mechanism of kohlrabi and provides a theoretical basis for the functional analysis of BocAP2/ERF transcription factor family members.

Upregulating KLF11 ameliorates intestinal inflammation in mice with 2, 4, 6-trinitrobenesulfonic acid-induced colitis by inhibiting the JAK2/STAT3 signaling pathway

To investigate the expression level of Kruppel-like transcription factor family member KLF11 in intestinal mucosal tissues of Crohn's disease (CD) and its regulatory effect on intestinal inflammation in CD-like colitis. We examined KLF11 expression levels in diseased and normal colon mucosal tissues from 12 CD patients and 12 patients with colorectal cancer using immunofluorescence staining. KLF11 expression was also detected in the colon mucosal tissues of a mouse model of 2, 4, 6-trinitrobenesulfonic acid (TNBS)-induced colitis. A recombinant adenoviral vector was used to upregulate KLF11 expression in the mouse models and the changes in intestinal inflammation was observed. A Caco-2 cell model with stable KLF11 overexpression was constructed by lentiviral infection. The effect of KLF11 overexpression on expressions of JAK2/STAT3 signaling pathway proteins was investigated using immunoblotting in both the mouse and cell models. The mouse models were treated with coumermycin A1, a JAK2/STAT3 signaling pathway agonist, and the changes in intestinal inflammatory responses were observed. The expression level of KLF11 was significantly lowered in both the clinical specimens of diseased colon mucosal tissues and the colon tissues of mice with TNBS-induced colitis (P < 0.05). Adenovirus-mediated upregulation of KLF11 significantly improved intestinal inflammation and reduced the expression levels of inflammatory factors in the intestinal mucosa of the colitis mouse models (P < 0.05). Overexpression of KLF11 significantly inhibited the expression levels of p-JAK2 and p-STAT3 in intestinal mucosal tissues of the mouse models and in Caco-2 cells (P < 0.05). Treatment with coumermycin A1 obviously inhibited the effect of KLF11 upregulation for improving colitis and significantly increased the expression levels of inflammatory factors in the intestinal mucosa of the mouse models (P < 0.05). KLF11 is downregulated in the intestinal mucosa in CD, and upregulation of KLF11 can improve intestinal inflammation and reduce the production of inflammatory factors probably by inhibiting the JAK2/STAT3 signaling pathway.