Ets Family Research Articles

The copper transporter, SLC31A1, transcriptionally activated by ELF3, imbalances copper homeostasis to exacerbate cisplatin-induced acute kidney injury through mitochondrial dysfunction

Acute kidney injury (AKI) is a common complication of cisplatin chemotherapy, which greatly limits its clinical effect and application. This study explored the function of solute Carrier Family 31 Member 1 (SLC31A1) in cisplatin-induced AKI and its possible mechanism. Mice and HK-2 cells were exposed to cisplatin to establish the in vivo and in vitro AKI models. Cell viability was detected by CCK-8. Mitochondrial and oxidative damage was determined by Mito-Tracker Green staining, mtROS level, ATP production, mitochondrial membrane potential, MDA content and CAT activity. AKI was evaluated by renal function and histopathological changes. Apoptosis was detected by TUNEL and caspase-3 expression. Molecule expression was measured by RT-qPCR, Western blotting, and immunohistochemistry. Molecular mechanism was studied by luciferase reporter assay and ChIP. SLC31A1 level was predominantly increased by cisplatin exposure in AKI models. Notably, copper ion (Cu+) level was enhanced by cisplatin challenge. Moreover, Cu+ supplementation intensified cisplatin-induced cell death, mitochondrial dysfunction, and oxidative stress in HK-2 cells, indicating the involvement of cuproptosis in cisplatin-induced AKI, whereas these changes were partially counteracted by SLC31A1 knockdown. E74 like ETS transcription factor 3 (ELF3) could directly bind to SLC31A1 promoter and promote its transcription. ELF3 was up-regulated and positively correlated with SLC31A1 expression upon cisplatin-induced AKI. SLC31A1 silencing restored renal function, alleviated mitochondrial dysfunction, and apoptosis in cisplatin-induced AKI mice. ELF3 transcriptionally activated SLC31A1 to trigger cuproptosis that drove cisplatin-induced AKI through mitochondrial dysfunction, indicating that SLC31A1 might be a promising therapeutic target to mitigate AKI during cisplatin chemotherapy.

Modeling of new markers for the diagnosis and prognosis of pancreatic cancer based on the transition from inflammation to cancer.

Pancreatic adenocarcinoma (PAAD) is a lethal disease with a poor prognosis. Genes involved in acute pancreatitis (AP) or chronic pancreatitis (CP) might be important for PAAD development. This study sought to identify potential PAAD diagnosis markers and to establish a PAAD prognosis prediction model based on AP- and CP-related genes. The significantly differentially expressed genes in both AP or CP and PAAD were obtained by a bioinformatics analysis. A risk-score model for predicting survival was constructed based on The Cancer Genome Atlas (TCGA) data and validated using an International Cancer Genome Consortium (ICGC) cohort. Protein expression and the effects of the genes in the risk models were validated by immunohistochemistry, or Cell Counting Kit-8 (CCK-8) and transwell assays. The study sample data included six AP tissue samples and five normal pancreatic tissue samples, six CP tissue samples and six normal pancreatic tissue samples from the Gene Expression Omnibus (GEO) expression profiling microarrays GSE109227 and GSE41418 data sets, respectively, and fragments per kilobase per million mapped fragments (FPKM) data from four normal controls and 150 PAAD cases from TCGA database, and 182 cancer patient samples with complete survival prognostic data from the ICGC database. In total, 508 significantly differentially expressed genes were found in both AP or CP and PAAD. Trefoil factor 2 (TFF2), tubulointerstitial nephritis antigen (TINAG), trefoil factor 1 (TFF1), aquaporin 5 (AQP5), SAM pointed domain containing ETS transcription factor (SPDEF), anterior gradient protein 2 (AGR2), apolipoprotein B messenger RNA editing enzyme catalytic subunit 1 (APOBEC1), kallikrein-related peptidase 6 (KLK6), dopa decarboxylase (DDC), mucin 13 (MUC13), claudin 18 (CLDN18), annexin A10 (ANXA10), and tetraspanin 1 (TSPAN1) were found to be present in PAAD and had the largest fold change. A risk-score model, comprising 19 genes, was constructed for prognostic prediction. A high-risk score indicated a poor prognosis. TINAG, DDC, SPDEF, and APOBEC1 proteins were increased in PAAD, while TINAG and DDC were correlated with the pathologic grade. Decreased TINAG, APOBEC1, transmembrane protein 94 (TMEM94), and kelch like family member 36 (KLHL36) expression inhibited PAAD cell proliferation, while decreased SPDEF, TMEM94, and KLHL36 expression significantly inhibited PAAD cell migration. The AP and CP co-related genes were significantly correlated with PAAD. TINAG, DDC, SPDEF, and APOBEC1 could serve as new PAAD predictors. The risk model developed in this study could be used to predict the prognosis of PAAD patients.

SOX17/ETV2 improves the direct reprogramming of adult fibroblasts to endothelial cells

An autologous source of vascular endothelial cells (ECs) is valuable for vascular regeneration and tissue engineering without the concern of immune rejection. The transcription factor ETS variant 2 (ETV2) has been shown to directly convert patient fibroblasts into vascular EC-like cells. However, reprogramming efficiency is low and there are limitations in EC functions, such as eNOS expression. In this study, we directly reprogram adult human dermal fibroblasts into reprogrammed ECs (rECs) by overexpressing SOX17 in conjunction with ETV2. We find several advantages to rEC generation using this approach, including improved reprogramming efficiency, increased enrichment of EC genes, formation of large blood vessels carrying blood from the host, and, most importantly, expression of eNOS invivo. From these results, we present an improved method to reprogram adult fibroblasts into functional ECs and posit ideas for the future that could potentially further improve the reprogramming process.

ETS transcription factors regulate precise matrix metalloproteinase expression and follicle rupture in Drosophila.

Drosophila matrix metalloproteinase 2 (MMP2) is specifically expressed in posterior follicle cells of stage-14 egg chambers (mature follicles) and is crucial for the breakdown of the follicular wall during ovulation, a process that is highly conserved from flies to mammals. The factors that regulate spatiotemporal expression of MMP2 in follicle cells remain unknown. Here, we demonstrate crucial roles for the ETS-family transcriptional activator Pointed (Pnt) and its endogenous repressor Yan in the regulation of MMP2 expression. We found that Pnt is expressed in posterior follicle cells and overlaps with MMP2 expression in mature follicles. Genetic analysis demonstrated that pnt is both required and sufficient for MMP2 expression in follicle cells. In addition, Yan was temporally upregulated in stage-13 follicle cells to fine-tune Pnt activity and MMP2 expression. Furthermore, we identified a 1.1 kb core enhancer that is responsible for the spatiotemporal expression of MMP2 and contains multiple pnt/yan binding motifs. Mutation of pnt/yan binding sites significantly impaired the Mmp2 enhancer activity. Our data reveal a mechanism of transcriptional regulation of Mmp2 expression in Drosophila ovulation, which could be conserved in other biological systems.

Spontaneous expression of the CIC::DUX4 fusion oncoprotein from a conditional allele potently drives sarcoma formation in genetically engineered mice.

CIC::DUX4 sarcoma (CDS) is a rare but highly aggressive undifferentiated small round cell sarcoma driven by a fusion between the tumor suppressor Capicua (CIC) and DUX4. Currently, there are no effective treatments and efforts to identify and translate better therapies are limited by the scarcity of patient tumor samples and cell lines. To address this limitation, we generated three genetically engineered mouse models of CDS (Ch7CDS, Ai9CDS, and TOPCDS). Remarkably, chimeric mice from all three conditional models developed spontaneous soft tissue tumors and disseminated disease in the absence of Cre-recombinase. The penetrance of spontaneous (Cre-independent) tumor formation was complete irrespective of bi-allelic Cic function and the distance between adjacent loxP sites. Characterization of soft tissue and presumed metastatic tumors showed that they consistently expressed the CIC::DUX4 fusion protein and many downstream markers of the disease credentialing the models as CDS. In addition, tumor-derived cell lines were generated and ChIP-seq was preformed to map fusion-gene specific binding using an N-terminal HA epitope tag. These datasets, along with paired H3K27ac ChIP-sequencing maps, validate CIC::DUX4 as a neomorphic transcriptional activator. Moreover, they are consistent with a model where ETS family transcription factors are cooperative and redundant drivers of the core regulatory circuitry in CDS.

Ehf and Fezf2 regulate late medullary thymic epithelial cell and thymic tuft cell development.

Thymic epithelial cells are indispensable for T cell maturation and selection and the induction of central immune tolerance. The self-peptide repertoire expressed by medullary thymic epithelial cells is in part regulated by the transcriptional regulator Aire (Autoimmune regulator) and the transcription factor Fezf2. Due to the high complexity of mTEC maturation stages (i.e., post-Aire, Krt10+ mTECs, and Dclk1+ Tuft mTECs) and the heterogeneity in their gene expression profiles (i.e., mosaic expression patterns), it has been challenging to identify the additional factors complementing the transcriptional regulation. We aimed to identify the transcriptional regulators involved in the regulation of mTEC development and self-peptide expression in an unbiased and genome-wide manner. We used ATAC footprinting analysis as an indirect approach to identify transcription factors involved in the gene expression regulation in mTECs, which we validated by ChIP sequencing. This study identifies Fezf2 as a regulator of the recently described thymic Tuft cells (i.e., Tuft mTECs). Furthermore, we identify that transcriptional regulators of the ELF, ESE, ERF, and PEA3 subfamily of the ETS transcription factor family and members of the Krüppel-like family of transcription factors play a role in the transcriptional regulation of genes involved in late mTEC development and promiscuous gene expression.

Vascular injury activates the ELK1/SND1/SRF pathway to promote vascular smooth muscle cell proliferative phenotype and neointimal hyperplasia

BackgroundVascular smooth muscle cell (VSMC) proliferation is the leading cause of vascular stenosis or restenosis. Therefore, investigating the molecular mechanisms and pivotal regulators of the proliferative VSMC phenotype is imperative for precisely preventing neointimal hyperplasia in vascular disease.MethodsWire-induced vascular injury and aortic culture models were used to detect the expression of staphylococcal nuclease domain-containing protein 1 (SND1). SMC-specific Snd1 knockout mice were used to assess the potential roles of SND1 after vascular injury. Primary VSMCs were cultured to evaluate SND1 function on VSMC phenotype switching, as well as to investigate the mechanism by which SND1 regulates the VSMC proliferative phenotype.ResultsPhenotype-switched proliferative VSMCs exhibited higher SND1 protein expression compared to the differentiated VSMCs. This result was replicated in primary VSMCs treated with platelet-derived growth factor (PDGF). In the injury model, specific knockout of Snd1 in mouse VSMCs reduced neointimal hyperplasia. We then revealed that ETS transcription factor ELK1 (ELK1) exhibited upregulation and activation in proliferative VSMCs, and acted as a novel transcription factor to induce the gene transcriptional activation of Snd1. Subsequently, the upregulated SND1 is associated with serum response factor (SRF) by competing with myocardin (MYOCD). As a co-activator of SRF, SND1 recruited the lysine acetyltransferase 2B (KAT2B) to the promoter regions leading to the histone acetylation, consequently promoted SRF to recognize the specific CArG motif, and enhanced the proliferation- and migration-related gene transcriptional activation.ConclusionsThe present study identifies ELK1/SND1/SRF as a novel pathway in promoting the proliferative VSMC phenotype and neointimal hyperplasia in vascular injury, predisposing the vessels to pathological remodeling. This provides a potential therapeutic target for vascular stenosis.Graphical abstract

Lhx3/4 initiates a cardiopharyngeal-specific transcriptional program in response to widespread FGF signaling.

Individual signaling pathways, such as fibroblast growth factors (FGFs), can regulate a plethora of inductive events. According to current paradigms, signal-dependent transcription factors (TFs), such as FGF/MapK-activated Ets family factors, partner with lineage-determining factors to achieve regulatory specificity. However, many aspects of this model have not been rigorously investigated. One key question relates to whether lineage-determining factors dictate lineage-specific responses to inductive signals or facilitate these responses in collaboration with other inputs. We utilize the chordate model Ciona robusta to investigate mechanisms generating lineage-specific induction. Previous studies in C. robusta have shown that cardiopharyngeal progenitor cells are specified through the combined activity of FGF-activated Ets1/2.b and an inferred ATTA-binding transcriptional cofactor. Here, we show that the homeobox TF Lhx3/4 serves as the lineage-determining TF that dictates cardiopharyngeal-specific transcription in response to pleiotropic FGF signaling. Targeted knockdown of Lhx3/4 leads to loss of cardiopharyngeal gene expression. Strikingly, ectopic expression of Lhx3/4 in a neuroectodermal lineage subject to FGF-dependent specification leads to ectopic cardiopharyngeal gene expression in this lineage. Furthermore, ectopic Lhx3/4 expression disrupts neural plate morphogenesis, generating aberrant cell behaviors associated with execution of incompatible morphogenetic programs. Based on these findings, we propose that combinatorial regulation by signal-dependent and lineage-determinant factors represents a generalizable, previously uncategorized regulatory subcircuit we term "cofactor-dependent induction." Integration of this subcircuit into theoretical models will facilitate accurate predictions regarding the impact of gene regulatory network rewiring on evolutionary diversification and disease ontogeny.

Integrative genomic analyses reveal putative cell type-specific targets of the Drosophila ets transcription factor Pointed

The Ets domain transcription factors direct diverse biological processes throughout all metazoans and are implicated in development as well as in tumor initiation, progression and metastasis. The Drosophila Ets transcription factor Pointed (Pnt) is the downstream effector of the Epidermal growth factor receptor (Egfr) pathway and is required for cell cycle progression, specification, and differentiation of most cell types in the larval eye disc. Despite its critical role in development, very few targets of Pnt have been reported previously. Here, we employed an integrated approach by combining genome-wide single cell and bulk data to identify putative cell type-specific Pnt targets. First, we used chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) to determine the genome-wide occupancy of Pnt in late larval eye discs. We identified enriched regions that mapped to an average of 6,941 genes, the vast majority of which are novel putative Pnt targets. Next, we integrated ChIP-seq data with two other larval eye single cell genomics datasets (scRNA-seq and snATAC-seq) to reveal 157 putative cell type-specific Pnt targets that may help mediate unique cell type responses upon Egfr-induced differentiation. Finally, our integrated data also predicts cell type-specific functional enhancers that were not reported previously. Together, our study provides a greatly expanded list of putative cell type-specific Pnt targets in the eye and is a resource for future studies that will allow mechanistic insights into complex developmental processes regulated by Egfr signaling.

BRCA1 and ELK-1 regulate neural progenitor cell fate in the optic tectum in response to visual experience in Xenopus laevis tadpoles.

In developing Xenopus tadpoles, the optic tectum begins to receive patterned visual input while visuomotor circuits are still undergoing neurogenesis and circuit assembly. This visual input regulates neural progenitor cell fate decisions such that maintaining tadpoles in the dark increases proliferation, expanding the progenitor pool, while visual stimulation promotes neuronal differentiation. To identify regulators of activity-dependent neural progenitor cell fate, we profiled the transcriptomes of proliferating neural progenitor cells and newly differentiated neurons using RNA-Seq. We used advanced bioinformatic analysis of 1,130 differentially expressed transcripts to identify six differentially regulated transcriptional regulators, including Breast Cancer 1 (BRCA1) and the ETS-family transcription factor, ELK-1, which are predicted to regulate the majority of the other differentially expressed transcripts. BRCA1 is known for its role in cancers, but relatively little is known about its potential role in regulating neural progenitor cell fate. ELK-1 is a multifunctional transcription factor which regulates immediate early gene expression. We investigated the potential functions of BRCA1 and ELK-1 in activity-regulated neurogenesis in the tadpole visual system using in vivo time-lapse imaging to monitor the fate of GFP-expressing SOX2+ neural progenitor cells in the optic tectum. Our longitudinal in vivo imaging analysis showed that knockdown of either BRCA1 or ELK-1 altered the fates of neural progenitor cells and furthermore that the effects of visual experience on neurogenesis depend on BRCA1 and ELK-1 expression. These studies provide insight into the potential mechanisms by which neural activity affects neural progenitor cell fate.

Trk Inhibition Reduces Tumorsphere Formation and Changes Expression of Stemness Markers in SK-ES-1 Ewing Sarcoma Cells

Introduction: Ewing sarcoma (ES) is a highly aggressive type of childhood cancer characterized by a chromosomal translocation resulting in fusions between the gene encoding EWS RNA Binding Protein 1 (EWSR1) and one gene of the ETS family, most frequently FLI-1, resulting in the EWS-FLI1 aberrant transcription factor. ES tumors can contain a subpopulation of cells showing cancer stem cell (CSC) features, which express stemness markers including CD133, OCT4 (Octamer-binding transcription factor 4), and NANOG, and display capacity to form tumorspheres likely enriched in CSCs. Neurotrophin (NT) receptors of the tropomyosin receptor kinase (Trk) family (TrkA, TrkB, and TrkC) may play a role in stimulating ES progression, but their possible role in CSCs remains unknown. Objective: To verify the effect of Trks inhibition on the formation of tumorspheres as well as the gene expression of stem markers. Method: The cells were dissociated and the formation of spheres was induced with supplemented culture medium and the K252a treatment was performed. After RNA extraction, mRNA expression levels of target genes Prom1 (CD133), OCT4 (POU5F1), SOX2, and Musashi-1 (MSI1) were analyzed by qPCR. Results: The pan-Trk inhibitor K252a (100 or 500 mM) hindered tumorsphere formation in human SK-ES-1 ES cell cultures. K252a also reduced mRNA expression of Prom1 (CD133-coding gene) while enhancing expression of OCT4. No changes in mRNA levels of SOX2 or Musashi-1 were observed. Conclusion: These findings provide the first evidence suggesting that Trk activity can influence stemness in ES cells.

Allele-specific effect of various dietary fatty acids and ETS1 transcription factor on SCD1 expression

Overnutrition and genetic predisposition are major risk factors for various metabolic disorders. Stearoyl-CoA desaturase-1 (SCD1) plays a key role in these conditions by synthesizing unsaturated fatty acids (FAs), thereby promoting fat storage and alleviating lipotoxicity. Expression of SCD1 is influenced by various saturated and cis-unsaturated FAs, but the possible role of dietary trans FAs (TFAs) and SCD1 promoter polymorphisms in its regulations has not been addressed. Therefore, we aimed to investigate the impact of the two main TFAs, vaccenate and elaidate, and four common promoter polymorphisms (rs1054411, rs670213, rs2275657, rs2275656) on SCD1 expression in HEK293T and HepG2 cell cultures using luciferase reporter assay, qPCR and immunoblotting. We found that SCD1 protein and mRNA levels as well as SCD1 promoter activity are markedly elevated by elaidate, but not altered by vaccenate. The promoter polymorphisms did not affect the basal transcriptional activity of SCD1. However, the minor allele of rs1054411 increased SCD1 expression in the presence of various FAs. Moreover, this variant was predicted in silico and verified in vitro to reduce the binding of ETS1 transcription factor to SCD1 promoter. Although we could not confirm an association with type 2 diabetes mellitus, the FA-dependent and ETS1-mediated effect of rs1054411 polymorphism deserves further investigation as it may modulate the development of lipid metabolism-related conditions.

Construction of gastric cancer prognostic signature based on the E26 transcription factor and the identification of novel oncogene ELK3.

The aim of the present study was to investigate the function of 29 E26 (ETS) transcription factor families in gastric cancer (GC) and determine their association with prognosis. Our analysis of the expression of the ETS family revealed that 28 genes were dysregulated in GC, and that their expression was associated with multiple clinicopathological features (P<0.05). Based on the expression signature of the ETS family, consensus clustering was performed to generate two gastric cancer subtypes. These subtypes exhibited differences in overall survival (OS, P = 0.161), disease-free survival (DFS, P<0.05) and GC grade (P<0.01). Functional enrichment analysis of the target genes associated with the ETS family indicated that these genes primarily contribute to functions that facilitate tumor progression. A systematic statistical analysis was used to construct a prognostic model related to OS and DFS in association with the ETS family. This model demonstrated that the maximum area under the curve (AUC) values for predicting OS and DFS were 0.729 and 0.670, respectively, establishing ETS as an independent prognostic factor for GC Furthermore, a nomogram was created from the prognostic signature, and its predictive accuracy was confirmed by a calibration curve. Finally, the expression and prognostic significance of the six genes comprising the model were also examined. Among these, ELK3 was found to be significantly overexpressed in GC clinical samples. Subsequent in vitro and in vivo studies verified that ELK3 regulates GC proliferation and metastasis, highlighting its potential as a therapeutic target for gastric cancer.

The Diverse Roles of ETV6 Alterations in B-Lymphoblastic Leukemia and Other Hematopoietic Cancers.

Genetic alterations of the repressive ETS family transcription factor gene ETV6 are recurrent in several categories of hematopoietic malignancy, including subsets of B-cell and T-cell acute lymphoblastic leukemias (B-ALL and T-ALL), myeloid neoplasms, and mature B-cell lymphomas. ETV6 is essential for adult hematopoietic stem cells (HSCs), contributes to specific functions of some mature immune cells, and plays a key role in thrombopoiesis as demonstrated by familial ETV6 mutations associated with thrombocytopenia and predisposition to hematopoietic cancers, particularly B-ALL. ETV6 appears to have a tumor suppressor role in several hematopoietic lineages, as demonstrated by recurrent somatic loss-of-function (LoF) and putative dominant-negative alterations in leukemias and lymphomas. ETV6 rearrangements contribute to recurrent fusion oncogenes such as the B-ALL-associated transcription factor (TF) fusions ETV6::RUNX1 and PAX5::ETV6, rare drivers such as ETV6::NCOA6, and a spectrum of tyrosine kinase gene fusions encoding hyperactive signaling proteins that self-associate via the ETV6 N-terminal pointed domain. Another subset of recurrent rearrangements involving the ETV6 gene locus appear to function primarily to drive overexpression of the partner gene. This review surveys what is known about the biochemical and genome regulatory properties of ETV6 as well as our current understanding of how alterations in these functions contribute to hematopoietic and nonhematopoietic cancers.

E74-like ETS transcription factor 1 promotes the progression of pancreatic cancer by regulating doublecortin-like kinase 1/Janus kinase/signal transducer and activator of transcription pathway

E74-like ETS transcription factor 1 promotes the progression of pancreatic cancer by regulating doublecortin-like kinase 1/Janus kinase/signal transducer and activator of transcription pathway

Huaier suppresses cell viability, migration and invasion in human non-small cell lung cancer via lncRNA DLEU2/miR-212-5p/ELF3 axis.

Accumulating studies suggest that Huaier exerts anti-tumor effects through intricate mechanisms. Despite extensive research on its efficacy in lung cancer, further investigation is required to elucidate the molecular mechanism of Huaier. The involvement of long noncoding RNAs (lncRNAs) in the anti-lung cancer effects of Huaier remains unknown. In this study, we found Huaier suppressed cell viability, migration and invasion in non-small cell lung cancer (NSCLC) cells. LncRNA sequencing analysis revealed Deleted in lymphocytic leukemia 2 (DLEU2) to be significantly downregulated in Huaier-treated NSCLC cells. Furthermore, DLEU2 silencing was observed to suppress NSCLC progression, while DLEU2 overexpression attenuated the anti-tumor effects of Huaier in NSCLC, thereby promoting cell viability, migration and invasion of NSCLC. The ceRNA role of DLEU2 had been demonstrated in NSCLC, which directly interacted with miR-212-5p to rescue the repression of E74 Like ETS Transcription Factor 3 (ELF3) by this microRNA. Additionally, Huaier was found to regulate the expression of miR-212-5p and ELF3. Functionally, miR-212-5p inhibitor or ELF3 overexpression reversed the effects of DLEU2 silencing or Huaier treatment, resulting in increased colony formation, migration and invasion in NSCLC. Taken together, these results illuminate the mechanism underlying Huaier's anti-tumor effects via the DLEU2/miR-212-5p/ELF3 signaling pathway, which offers novel insights into the anti-tumor effects of Huaier and constitutes a promising therapeutic target for the treatment in NSCLC.

The roles and mechanisms of ETS1 in autoimmune diseases and cancers: A comprehensive review

E26 transformation-specific-1 (ETS1) is a founding member of the ETS transcription factor family. This transcription factor is highly conserved in amino acid sequences and highly expressed in many immune tissues, such as the thymus, spleen, and lymph gland. ETS1 plays multiple regulatory roles in immune-related diseases and acts as a transcriptional activator or inhibitor of many genes to regulate immune cell differentiation, development, apoptosis, and tumor occurrence. The expression level of ETS1 is correlated with disease severity. However, the molecular mechanisms behind disease and tumor progression mediated by ETS1 have not been fully elucidated. In addition, the therapeutic potential of ETS1 in clinical treatment remains to be further explored. Here, we review and summarize the molecular structure and functions of ETS1 and then focus on the roles of ETS1 in the occurrence of autoimmune diseases and cancers. This review provides a reference corroborating ETS1 as a potential therapeutic target for immune-related diseases and cancers.

Club cell CREB regulates the goblet cell transcriptional network and pro-mucin effects of IL-1B.

Introduction: Club cells are precursors for mucus-producing goblet cells. Interleukin 1β (IL-1B) is an inflammatory mediator with pro-mucin activities that increases the number of mucus-producing goblet cells. IL-1B-mediated mucin production in alveolar adenocarcinoma cells requires activation of the cAMP response element-binding protein (CREB). Whether the pro-mucin activities of IL-1B require club cell CREB is unknown. Methods: We challenged male mice with conditional loss of club cell Creb1 and wild type littermates with intra-airway IL-1B or vehicle. Secondarily, we studied human "club cell-like" H322 cells. Results: IL-1B increased whole lung mRNA of secreted (Mucin 5ac, Mucin 5b) and tethered (Mucin 1, Mucin 4) mucins independent of genotype. However, loss of club cell Creb1 increased whole lung mRNA of member RAS oncogene family (Rab3D), decreased mRNA of the muscarinic receptor 3 (M3R) and prevented IL-1B mediated increases in purinergic receptor P2Y, (P2ry2) mRNA. IL-1B increased the density of goblet cells containing neutral mucins in wildtype mice but not in mice with loss of club cell Creb1. These findings suggested that club cell Creb1 regulated mucin secretion. Loss of club cell Creb1 also prevented IL-1B-mediated impairments in airway mechanics. Four days of pharmacologic CREB inhibition in H322 cells increased mRNA abundance of forkhead box A2 (FOXA2), a repressor of goblet cell expansion, and decreased mRNA expression of SAM pointed domain containing ETS transcription factor (SPDEF), a driver of goblet cell expansion. Chromatin immunoprecipitation demonstrated that CREB directly bound to the promoter region of FOXA2, but not to the promoter region of SPDEF. Treatment of H322 cells with IL-1B increased cAMP levels, providing a direct link between IL-1B and CREB signaling. Conclusion: Our findings suggest that club cell Creb1 regulates the pro-mucin properties of IL-1B through pathways likely involving FOXA2.

Mesenchymal and Vascular Dissemination Markers, Erythroblastosis Virus E26 Oncogene Homolog (ERG) and Alpha Smooth Muscle Actin (α-SMA), in Colorectal Cancer and Adjacent Tissue, Pericytes or Microvascular Density.

The harmony between malignant cells and the adjacent microenvironment is a sophisticated subject; however, it seems to play an important role in cancer evolution. This study aimed to assess the microvascular density (MVD) and the mean pericyte number in the tumor and adjacent tissue, and to correlate the results with special histopathological prognostic variables of the tumor. The study included 48 colorectal cancer (CRC) cases diagnosed in the central lab of Duhok. The immunohistochemical (IHC) expressions of the mesenchymal and vascular dissemination markers, erythroblastosis virus E26 oncogene homolog (ERG, a member of the ETS family of transcription factors) and alpha smooth muscle actin (α-SMA) for microvascular density and pericytes, were assessed in tumor cells and in adjacent tissue around the tumor and then correlated to clinicopathological variables with a special concentration on inflammatory reaction, tumor budding, tumor deposition, and lymphovascular invasion. The results showed that the MVD was significantly higher outside the tumor in T1 and T2 compared with T3 and T4.Moreover, it was significantly higher in grade I when compared to grades II and III within the tumor.However, no correlation was found between the MVD and the special histopathological variables that had been studied. On the other hand, the low mean pericyte showed multiple significant associations outside tumor areas, with special histopathological features including a severe inflammatory reaction, a positive tumor deposit, and a negative lymphovascular invasion. These findings may indicate that defective or transformed pericytes around the tumor can participate in the development of the tumor and, subsequently, the outcome and prognosis.

Biological, prognostic, and therapeutic impact of the epigenome in CLL

Chronic lymphocytic leukemia (CLL) is characterized by widespread alterations in the genetic and epigenetic landscapes which seem to underlie the variable clinical manifestations observed in patients. Over the last decade, epigenomic studies have described the whole-genome maps of DNA methylation and chromatin features of CLL and normal B cells, identifying distinct epigenetic mechanisms operating in tumoral cells. DNA methylation analyses have identified that the CLL methylome contains imprints of the cell of origin, as well as of the proliferative history of the tumor cells, with both being strong independent prognostic predictors. Moreover, single-cell analysis revealed a higher degree of DNA methylation noise in CLL cells, which associates with transcriptional plasticity and disease aggressiveness. Integrative analysis of chromatin has uncovered chromatin signatures, as well as regulatory regions specifically active in each CLL subtype or in Richter transformed samples. Unique transcription factor (TF) binding motifs are overrepresented on those regions, suggesting that altered TF networks operate from disease initiation to progression as nongenetic factors mediating the oncogenic transcriptional profiles. Multiomics analysis has identified that response to treatment is modulated by an epigenetic imprint, and that treatments affect chromatin through the activity of particular set of TFs. Additionally, the epigenome is an axis of therapeutic vulnerability in CLL, as it can be targeted by inhibitors of histone modifying enzymes, that have shown promising preclinical results. Altogether, this review aims at summarizing the major findings derived from published literature to distill how altered epigenomic mechanisms contribute to CLL origin, evolution, clinical behavior, and response to treatment.