Explore the vast range of titles available.

Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health 1 . This is compounded by the limited efficacy of available treatments 1 and high failure rates during drug development 2 , highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22—which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu’s arteritis 3 – 6 —we identify that the causal gene, ETS2 , is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures 7 , we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities. ETS2 —which is associated with inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu’s arteritis—is a central regulator of human inflammatory macrophages.

Cancer-associated fibroblasts (CAFs) are known to promote angiogenesis in oral squamous cell carcinoma (OSCC). However, the epigenetic mechanisms through which CAFs facilitate angiogenesis within the tumor microenvironment are still poorly characterized. Nicotinamide N’-methyltransferase (NNMT), a member of the N-methyltransferase family, was found to be a key molecule in the activation of CAFs. This study shows that NNMT in fibroblasts contributes to angiogenesis and tumor growth through an epigenetic reprogramming-ETS2-VEGFA signaling axis in OSCC. Single-cell RNA Sequencing (scRNA-seq) analysis suggests that NNMT is mainly highly expressed in fibroblasts of head and neck squamous cell carcinoma (HNSCC). Moreover, analysis of the TCGA database and multiple immunohistochemical staining of clinical samples also identified a positive correlation between NNMT and tumor angiogenesis. This research further employed an assembled organoid model and a fibroblast-endothelial cell co-culture model to authenticate the proangiogenic ability of NNMT. At the molecular level, high expression of NNMT in CAFs was found to promote ETS2 expression by regulating H3K27 methylation level through mediating methylation deposition. Furthermore, ETS2 was verified to be an activating transcription factor of VEGFA in this study. Collectively, our findings delineate an epigenetic molecular regulatory network of angiogenesis and provide a theoretical basis for exploring new targets and clinical strategy in OSCC.

Despite advancements in thyroid cancer (THCA) treatment, the prognosis for advanced cases remains poor. Cellular senescence is crucial in tumor progression, with ETS2 emerging as a key regulator. However, the role of ETS2 and its interaction with ZMYND11 in THCA is unclear. Differentially expressed genes (DEGs) connected with cellular senescence were determined from The Cancer Genome Atlas (TCGA)-THCA dataset. Functional analysis, prognostic risk model, and nomogram were then performed to identify ETS2 as a hub gene. The roles of ETS2 and ZMYND11 were explored using Western blotting (WB), co-immunoprecipitation (Co-IP), and quantitative real-time polymerase chain reaction (qRT-PCR). Effects of ETS2 overexpression and knockdown of ZMYND11 on apoptosis, cell proliferation, epithelial-mesenchymal transition (EMT), and mTOR signaling were evaluated. In vivo, a xenograft model was established using Cal-62 cells with or without ETS2 overexpression to assess tumor growth and protein expression. ETS2 was notably downregulated in THCA, and its low expression was connected to adverse prognosis. ETS2 overexpression inhibited THCA cell invasion, migration, proliferation, and induced apoptosis. ETS2 also regulated the expression of EMT markers, indicating its role in inhibiting THCA progression. Co-IP analysis showed that ETS2 interacted with ZMYND11. Knockdown of ZMYND11 attenuated the inhibitory effect of ETS2 on THCA cell behavior and mTOR pathway regulation. In vivo, ETS2 overexpression reduced tumor growth and increased ETS2 and ZMYND11 expression in xenograft tumors. This study identified the cellular senescence gene ETS2 as a tumor suppressor in THCA, which interacts with ZMYND11 to regulate THCA tumor progression through the mTOR pathway, thereby inhibiting cell senescence. Targeting the ETS2-ZMYND1 axis may provide new therapeutic strategies and prognostic biomarkers for THCA.

Abnormal activities of distal cis-regulatory elements (CREs) contribute to the initiation and progression of cancer. Gain of super-enhancer (SE), a highly active distal CRE, is essential for the activation of key oncogenes in various cancers. However, the mechanism of action for most tumor-specific SEs still largely remains elusive. Here, we report that a candidate oncogene ETS2 was activated by a distal SE in inflammatory bowel disease (IBD) and colorectal cancer (CRC). The SE physically interacted with the ETS2 promoter and was required for the transcription activation of ETS2 . Strikingly, the ETS2 -SE activity was dramatically upregulated in both IBD and CRC tissues when compared to normal colon controls and was strongly correlated with the level of ETS2 expression. The tumor-specific activation of ETS2 -SE was further validated by increased enhancer RNA transcription from this region in CRC. Intriguingly, a known IBD-risk SNP resides in the ETS2 -SE and the genetic variant modulated the level of ETS2 expression through affecting the binding of an oncogenic transcription factor MECOM. Silencing of MECOM induced significant downregulation of ETS2 in CRC cells, and the level of MECOM and ETS2 correlated well with each other in CRC and IBD samples. Functionally, MECOM and ETS2 were both required for maintaining the colony-formation and sphere-formation capacities of CRC cells and MECOM was crucial for promoting migration. Taken together, we uncovered a novel disease-specific SE that distantly drives oncogenic ETS2 expression in IBD and CRC and delineated a mechanistic link between non-coding genetic variation and epigenetic regulation of gene transcription.

Glioblastoma is a highly aggressive brain tumour that creates an immunosuppressive microenvironment. Microglia, the brain’s resident immune cells, play a crucial role in this environment. Glioblastoma cells can reprogramme microglia to create a supportive niche that promotes tumour growth. However, the mechanisms controlling the acquisition of a transcriptome associated with a tumour-supportive microglial reactive state are not fully understood. In this study, we investigated changes in the transcriptional profile of BV2 microglia exposed to C6 glioma cells. RNA-sequencing analysis revealed a significant upregulation of microglial inhibitor of DNA binding 1 ( Id1 ) and Id2 , helix-loop-helix negative transcription regulatory factors. The concomitant regulation of microglial ETS proto-oncogene 2, transcription factor (ETS2)-target genes, i.e ., Dusp6 , Fli1 , Jun , Hmox1 , and Stab1 , led us to hypothesize that ETS2 could be regulated by ID proteins. In fact, ID2-ETS2 protein interactions increased in microglia exposed to glioma cells. In addition, perturbation of the ID2-ETS2 transcriptional axis influenced the acquisition of a microglial tumour-supportive phenotype. ID2 and ETS2 genes were found to be expressed by the tumour-associated microglia isolated from human glioblastoma tumour biopsies. Furthermore, ID2 and ETS2 gene expressions exhibited inverse prognostic values in patients with glioma in cohorts from The Cancer Genome Atlas. Collectively, our findings indicate that the regulation of ETS2 by ID2 plays a role in the transcriptional regulation of microglia in response to stimuli originating from glioblastoma cells, information that could lead to developing therapeutic strategies to manipulate microglial tumour-trophic functions.

Background ETS2 has been identified as a pivotal regulator in the development of human inflammatory diseases. Nevertheless, the functional aspects of ETS2 in asthma remain inadequately characterized. The release of mitochondrial dsRNA is recognized as an initiator of innate immune responses and implicated in intensifying inflammation triggered by alternative immunogens. The interplay between these mechanisms remains poorly understood, and only a limited number of direct targets that underpin the pro-inflammatory role of ETS2 have been identified. Methods The expression of ETS2 in epithelial cells under immune responses was analyzed, and its effects on asthma progression were examined through clinical specimens, human bronchial epithelial cells, and an allergic asthma mouse model. Additionally, the potential involvement of adenine nucleotide translocase-2 in mediating the immune responses regulated by ETS2 was explored. Results Increased expression of ETS2 in lung epithelial cells was observed in both asthma patients and ovalbumin (OVA)-induced asthma mice. The deficiency of ETS2 resulted in a substantial decline in inflammatory cell infiltration and markedly diminished IL-6, IL-5, and IL-13 levels in epithelial cells. Mechanistically, ETS2 overexpression was associated with elevated cytosolic mitochondrial RNA levels, whereas knockdown resulted in their suppression. Furthermore, adenine nucleotide translocase-2 (ANT2) expression was robustly upregulated by ETS2 through direct promoter binding. The advantageous effects of ETS2 on asthma development were abrogated in ANT2-deficient mice. Conclusions The findings collectively underscore the role of ETS2 as an exacerbating factor in allergic airway inflammation during asthma progression, primarily by inducing ANT2 expression. Therapeutic targeting of epithelial ETS2 could represent a novel approach to asthma management. Clinical trial number Not applicable.

Epithelial-to-mesenchymal transition (EMT) plays an important role in the progression of renal tubulointerstitial fibrosis, a common mechanism leading to end-stage renal failure. V-ets erythroblastosis virus E26 oncogene homolog 2 (ETS2), a transcription factor, exhibits diverse roles in pathogenesis; however, its role in renal fibrosis is not yet fully understood. In this study, we detected the expression of ETS2 in an animal model of renal fibrosis and evaluated the potential role of ETS2 in tubular EMT induced by TGF-β1. We found that ETS2 and profibrogenic factors, alpha-smooth muscle actin (α-SMA) and fibronectin (FN), were significantly increased in the unilateral ureteral obstruction (UUO)-induced renal fibrosis model in mice. In vitro, TGF-β1 induced a high expression of ETS2 dependent on Smad3 and ERK signaling pathway in human proximal tubular epithelial cells (HK2). Knockdown of ETS2 abrogated TGF-β1-mediated expression of profibrogenic factors vimentin, α-SMA, collagen I, and FN in HK2 cells. Mechanistically, ETS2 promoted JUNB expression in HK2 cells after TGF-β1 stimulation. Furthermore, luciferase and Chromatin Immunoprecipitation (ChIP) assays revealed that the binding of ETS2 to three EBS motifs on the promoter of JUNB triggered its transcription. Notably, silencing JUNB reversed the ETS2-induced upregulation of the profibrogenic factors in HK2 cells after TGF-β1 stimulation. These findings suggest that ETS2 mediates TGF-β1-induced EMT in renal tubular cells through JUNB, a novel pathway for preventing renal fibrosis.

Chronic liver injury results in activation of quiescent hepatic stellate cells (HSCs) into collagen type I–producing activated HSCs that make the liver fibrotic. We identified ETS1 and ETS2 (ETS1/2) as lineage-specific transcription factors regulating HSC phenotypes. Here, we investigated the role of ETS1/2 in HSCs in liver fibrosis using toxic liver injury models and 3D human liver spheroids. Liver fibrosis was induced in WT and HSC-specific Ets1-KO ( Ets1 ΔHSC ) and Ets2-KO ( Ets2 ΔHSC ) mice by administration of CCl 4 for 6 weeks, followed by cessation of liver injury for 2 weeks. Liver fibrosis was more severe in Ets1 ΔHSC and to a lesser extent Ets2 ΔHSC mice compared with WT mice. Regression of liver fibrosis was suppressed only in Ets1 ΔHSC mice, indicating Ets1 is the predominant isoform maintaining a quiescent-like phenotype in HSCs. Similar results were obtained in a metabolic dysfunction–associated steatohepatitis (MASH) model using 3D human liver spheroids. Knockdown of ETS1 in human HSCs caused upregulation of fibrogenic genes in MASH human liver spheroids and prevented fibrosis regression. ETS1 regulated the quiescent HSC phenotype via the CREB-regulated transcription coactivator 2 (CRTC2)/PGC1α/PPARγ pathway. Knockdown of CRTC2 abrogated PPARγ responses and facilitated HSC activation. These findings suggest that ETS1 may represent a therapeutic target for antifibrotic therapy.

The ETS-family transcription factors Ets1 and Ets2 are evolutionarily conserved effectors of the RAS/ERK signaling pathway, but their function in Ras cellular transformation and biology remains unclear. Taking advantage of Ets1 and Ets2 mouse models to generate Ets1/Ets2 double knockout mouse embryonic fibroblasts, we demonstrate that deletion of both Ets1 and Ets2 was necessary to inhibit HrasG12V induced transformation both in vitro and in vivo. HrasG12V expression in mouse embryonic fibroblasts increased ETS1 and ETS2 expression and binding to cis-regulatory elements on the c-Myc proximal promoter, and consequently induced a robust increase in MYC expression. The expression of the oncogenic microRNA 17-92 cluster was increased in HrasG12V transformed cells, but was significantly reduced when ETS1 and ETS2 were absent. MYC and ETS1 or ETS2 collaborated to increase expression of the oncogenic microRNA 17-92 cluster in HrasG12V transformed cells. Enforced expression of exogenous MYC or microRNA 17-92 rescued HrasG12V transformation in Ets1/Ets2-null cells, revealing a direct function for MYC and microRNA 17-92 in ETS1/ETS2-dependent HrasG12V transformation.