Aberrant Epigenetic Regulation Research Articles

Comparative Analysis of Circular RNAs Expression and Function between Aortic and Intracranial Aneurysms.

An aneurysm is an abnormal enlargement or bulging of the wall of a blood vessel. Most often, aneurysms occur in large blood vessels - the aorta (Thoracic Aortic Aneurysm (TAA) and Abdominal Aortic Aneurysm (AAA) and brain vessels (Intracranial Aneurysm (IA)). Despite the presence of significant differences in the pathogenesis of the development and progression of IA and TAA/AAA, there are also similarities. For instance, both have been shown to be strongly influenced by shear stress, inflammatory processes, and enzymatic destruction of the elastic lamellae and extracellular matrix (ECM) proteins of the vascular wall. Moreover, although IA and TAA are predominantly considered arteriopathies with different pathological mechanisms, they share risk factors with AAA, such as hypertension and smoking. However, there is a need for a more in- -depth study of the key elements that may influence the formation and progression of a particular aneurysm to find ways of therapeutic intervention or search for a diagnostic tool. Today, it is known that the disruption of gene expression is one of the main mechanisms that contribute to the development of aneurysms. At the same time, growing evidence suggests that aberrant epigenetic regulation of gene function is strongly related to the genesis of aneurysms. Although much has been studied of the known protein-coding genes, circular RNAs (circRNAs), a relatively new and rapidly evolving large family of transcripts, have recently received much scientific attention. CircRNAs regulate gene expression through the sponging of microRNAs (miRNAs) and can also be used as therapeutic targets and biomarkers. Increasing evidence has implicated circRNAs in the pathogenesis of multiple cardiovascular diseases, including the development of aneurysms. However, the mechanism of dysregulation of certain circRNAs in a particular aneurysm remains to be studied. The discovery of circRNAs has recently advanced our understanding of the latest mode of miRNAs/target genes regulation in the development and progression of IA and TAA/AAA. The aim of this study is to compare the expression profiles of circRNAs to search for similar or different effects of certain circRNAs on the formation and progression of IA and TAA/AAA.

Unlocking epigenetics for precision treatment of Ewing's sarcoma.

Ewing's sarcoma (EWS) is a highly aggressive malignant bone tumor primarily affecting adolescents and young adults. Despite the efficacy of chemoradiotherapy in some cases, the cure rate for patients with metastatic and recurrent disease remains low. Therefore, there is an urgent need for innovative therapeutic approaches to address the challenges associated with EWS treatment. Epigenetic regulation, a crucial factor in physiological processes, plays a significant role in controlling cell proliferation, maintaining gene integrity, and regulating transcription. Recent studies highlight the importance of abnormal epigenetic regulation in the initiation and progression of EWS. A comprehensive understanding of the intricate interactions between EWS and aberrant epigenetic regulation is essential for advancing clinical drug development. This review aims to provide a comprehensive overview of both epigenetic targets implicated in EWS, integrating various therapeutic modalities to offer innovative perspectives for the clinical diagnosis and treatment of EWS.

DIPG-24. COMBINED EPIGENETIC THERAPY WITH FACT AND BET INHIBITORS REMODELS CHROMATIN AND DISRUPTS ONCOGENIC TRANSCRIPTION IN DIFFUSE MIDLINE GLIOMA

Abstract BACKGROUND Aberrant epigenetic regulation is a hallmark of Diffuse Midline Glioma (DMG), an incurable pediatric brain tumor. The H3K27M driver histone mutation leads to transcriptional dysregulation, indicating that targeting the epigenome and transcription may be a key therapeutic strategy against this aggressive cancer. One such target is the Facilitates Chromatin Transcription (FACT) histone chaperone. FACT is targeted by the curaxin compound CBL0137 which is currently in Phase I/II Children’s Oncology Group clinical trial as a single agent for pediatric cancer patients (NCT04870944). METHODS We applied a multi-omics approach by integrating epigenetic profiling with transcriptomics (CUT&RUN, ATAC-seq and RNA-seq) to interrogate the role of FACT in DMG. We then employed in vitro cytotoxicity assays and in vivo orthotopic patient-derived xenograft (PDX) pre-clinical models to test a novel, mechanistic-anchored epigenetic combination therapy. RESULTS We found FACT to be enriched at developmental gene promoters, coinciding with regions of open chromatin and binding motifs of core DMG regulatory transcription factors (OLIG2, TCF12, and SNAI1). FACT interacted and co-localized with the Bromodomain and Extra-Terminal Domain (BET) protein BRD4 at active promoters and enhancers, suggesting functional cooperation between FACT and BRD4 in DMG. Investigating the combination of CBL0137 with two BET inhibitors (JQ1 and trotabresib) revealed potent cytotoxicity in vitro, particularly against H3K27M-mutant cells. Furthermore, this approach was recapitulated in vivo, significantly extending the survival of three independent orthotopic PDX models of DMG. Mechanistically, CBL0137 decreased chromatin accessibility, synergising with BET inhibition to disrupt transcription, leading to transcriptional silencing of several key oncogenes (MYC, PDGFRA and MDM4) as well as causing alterations to the splicing landscape. CONCLUSIONS This study highlights the therapeutic promise of simultaneously targeting FACT and BRD4 in DMG, and provides the rationale for a combination clinical trial, currently in development.

Oxidative stress contributes to hypermethylation of Histone H3 lysine 9 in placental trophoblasts from preeclamptic pregnancies.

Aberrant epigenetic regulation and increased oxidative stress in the placenta play a significant role in placental pathophysiology and fetal programming in preeclampsia, a hypertensive disorder in human pregnancy. The purpose of the study is to investigate if hypermethylation of histone H3K9 occurs in placental trophoblasts from preeclampsia. Trophoblasts were isolated and cultured from 14 placentas, 7 from normotensive pregnant women and 7 from preeclamptic pregnancies. Methylated H3K9 expression and antioxidant superoxide dismutase expression were determined by Western blot. We also examined consequences of oxidative stress and the downstream effects of histone methyltransferase inhibition on H3K9 expression associated with antioxidant CuZn-SOD and Mn-SOD expression in placental trophoblasts. We found that expression of mono-, di-, and tri-methylation of histone H3 lysine 9 (H3K9me1, H3K9me2 and H3K9me3) was significantly increased, p<0.01, which correlated with downregulation of antioxidant superoxide dismutase CuZn-SOD and Mn-SOD expression, in trophoblasts from preeclamptic placentas compared to those from uncomplicated control placentas. We further demonstrated hypoxia could promote histone H3K9 methylation in placental trophoblasts, and hypoxia-induced upregulation of H3K9me1, H3K9me2 and H3K9me3 expression was reversible when hypoxic condition was removed. In addition, we also uncovered that inhibition of methyltransferase not only prevented hypoxia-induced upregulation of H3K9me1, H3K9me2 and H3K9me3 expression, but also abolished hypoxia-induced downregulation of CuZn-SOD and Mn-SOD expression in placental trophoblasts. These findings are noteworthy and provide further evidence that increased oxidative stress in the intrauterine environment is likely a mechanism to induce aberrant histone modification in placental trophoblasts in preeclampsia. Moreover, CuZn-SOD and Mn-SOD expression/activity are possibly H3K9 methylation-dependent in placental trophoblasts, which further suggest that oxidative stress and aberrant histone modification have significant impact on placental trophoblasts/fetal programming in preeclampsia.

Molecular complexity of diffuse large B-cell lymphoma: a molecular perspective and therapeutic implications.

Diffuse large B-cell lymphoma (DLBCL) stands as a formidable challenge in the landscape of non-Hodgkin's lymphomas. This review illuminates the remarkable strides made in comprehending DLBCL's molecular intricacies and devising targeted treatments. DLBCL, the most prevalent non-Hodgkin's lymphoma, has seen transformative progress in its characterization. Genetic investigations, led by high-throughput sequencing, have unveiled recurrent mutations in genes such as MYC, BCL2, and BCL6, casting light on the underlying genetic chaos propelling DLBCL's aggressiveness. A pivotal facet of this understanding centers on cell signaling pathways. Dysregulation of B-cell receptor (BCR) signaling, NF-κB, PI3K/Akt/mTOR, JAK/STAT, Wnt/β-Catenin, and Toll-like receptor pathways plays a critical role in DLBCL pathogenesis, offering potential therapeutic targets. DLBCL's complex tumor microenvironment (TME) cannot be overlooked. The dynamic interplay among tumor cells, immune cells, stromal components, and the extracellular matrix profoundly influences DLBCL's course and response to therapies. Epigenetic modifications, including DNA methylation and histone changes, add another layer of intricacy. Aberrant epigenetic regulation plays a significant role in lymphomagenesis, offering prospects for epigenetic-based therapies. Promisingly, these molecular insights have spurred the development of personalized treatments. Targeted therapies and immunotherapies, guided by genomic profiling and molecular classification, are emerging as game-changers in DLBCL management. In conclusion, this review underscores the remarkable strides in understanding DLBCL's molecular underpinnings, spanning genetics, cell signaling, the tumor microenvironment, and epigenetics. These advances pave the way for more effective, personalized treatments, renewing hope for DLBCL patients.

Lineage plasticity and treatment resistance in prostate cancer: the intersection of genetics, epigenetics, and evolution.

Androgen deprivation therapy is a cornerstone of treatment for advanced prostate cancer, and the development of castrate-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-related mortality. While CRPC typically develops through a gain in androgen receptor (AR) signaling, a subset of CRPC will lose reliance on the AR. This process involves genetic, epigenetic, and hormonal changes that promote cellular plasticity, leading to AR-indifferent disease, with neuroendocrine prostate cancer (NEPC) being the quintessential example. NEPC is enriched following treatment with second-generation anti-androgens and exhibits resistance to endocrine therapy. Loss of RB1, TP53, and PTEN expression and MYCN and AURKA amplification appear to be key drivers for NEPC differentiation. Epigenetic modifications also play an important role in the transition to a neuroendocrine phenotype. DNA methylation of specific gene promoters can regulate lineage commitment and differentiation. Histone methylation can suppress AR expression and promote neuroendocrine-specific gene expression. Emerging data suggest that EZH2 is a key regulator of this epigenetic rewiring. Several mechanisms drive AR-dependent castration resistance, notably AR splice variant expression, expression of the adrenal-permissive 3βHSD1 allele, and glucocorticoid receptor expression. Aberrant epigenetic regulation also promotes radioresistance by altering the expression of DNA repair- and cell cycle-related genes. Novel therapies are currently being developed to target these diverse genetic, epigenetic, and hormonal mechanisms promoting lineage plasticity-driven NEPC.

Epigenetic Regulation of Leukocyte Inflammatory Mediator Production Dictates Staphylococcus aureus Craniotomy Infection Outcome.

Staphylococcus aureus is a common cause of surgical-site infections, including those arising after craniotomy, which is performed to access the brain for the treatment of tumors, epilepsy, or hemorrhage. Craniotomy infection is characterized by complex spatial and temporal dynamics of leukocyte recruitment and microglial activation. We recently identified unique transcriptional profiles of these immune populations during S. aureus craniotomy infection. Epigenetic processes allow rapid and reversible control over gene transcription; however, little is known about how epigenetic pathways influence immunity to live S. aureus. An epigenetic compound library screen identified bromodomain and extraterminal domain-containing (BET) proteins and histone deacetylases (HDACs) as critical for regulating TNF, IL-6, IL-10, and CCL2 production by primary mouse microglia, macrophages, neutrophils, and granulocytic myeloid-derived suppressor cells in response to live S. aureus. Class I HDACs (c1HDACs) were increased in these cell types in vitro and in vivo during acute disease in a mouse model of S. aureus craniotomy infection. However, substantial reductions in c1HDACs were observed during chronic infection, highlighting temporal regulation and the importance of the tissue microenvironment for dictating c1HDAC expression. Microparticle delivery of HDAC and BET inhibitors in vivo caused widespread decreases in inflammatory mediator production, which significantly increased bacterial burden in the brain, galea, and bone flap. These findings identify histone acetylation as an important mechanism for regulating cytokine and chemokine production across diverse immune cell lineages that is critical for bacterial containment. Accordingly, aberrant epigenetic regulation may be important for promoting S. aureus persistence during craniotomy infection.

Aberrant epigenetic regulation of FZD3 by TET2 is involved in ovarian cancer cell resistance to cisplatin

A major challenge in platinum-based cancer therapy, including cisplatin (DDP), is the clinical management of chemo-resistant tumours, which have unknown pathogenesis at the level of epigenetic mechanism. To identify potential resistance mechanisms, we integrated ovarian cancers (OC)-related GEO database retrieval and prognostic analyses. The results of bioinformatics prediction showed that frizzled class receptor 3 (FZD3) was a DDP-associated gene and closely related to the prognosis of OC. DDP resistance in OC inhibited FZD3 expression. FZD3 reduced DDP resistance in OC cells, increased the inhibitory effect of DDP on the growth and aggressiveness of DDP-resistant cells, and promoted apoptosis and DNA damage. TET2 was reduced in OC. TET2 promoted the transcription of FZD3 through DNA hydroxymethylation. TET2 sensitized the drug-resistant cells to DDP in vitro and in vivo, and the ameliorating effect of TET2 on drug resistance was significantly reversed after the inhibition of FZD3. Our findings reveal a previously unknown epigenetic axis TET2/FZD3 suppression as a potential resistance mechanism to DDP in OC.

The Epigenetic Reader Methyl-CpG-Binding Protein 2 (MeCP2) Is an Emerging Oncogene in Cancer Biology.

Epigenetic mechanisms are gene regulatory processes that control gene expression and cellular identity. Epigenetic factors include the "writers", "readers", and "erasers" of epigenetic modifications such as DNA methylation. Accordingly, the nuclear protein Methyl-CpG-Binding Protein 2 (MeCP2) is a reader of DNA methylation with key roles in cellular identity and function. Research studies have linked altered DNA methylation, deregulation of MeCP2 levels, or MECP2 gene mutations to different types of human disease. Due to the high expression level of MeCP2 in the brain, many studies have focused on its role in neurological and neurodevelopmental disorders. However, it is becoming increasingly apparent that MeCP2 also participates in the tumorigenesis of different types of human cancer, with potential oncogenic properties. It is well documented that aberrant epigenetic regulation such as altered DNA methylation may lead to cancer and the process of tumorigenesis. However, direct involvement of MeCP2 with that of human cancer was not fully investigated until lately. In recent years, a multitude of research studies from independent groups have explored the molecular mechanisms involving MeCP2 in a vast array of human cancers that focus on the oncogenic characteristics of MeCP2. Here, we provide an overview of the proposed role of MeCP2 as an emerging oncogene in different types of human cancer.

The emergence and destiny of automated methods to differentiate wide QRS complex tachycardias

Cancer is a disease related to uncontrolled growth and spreading of affected cells via a blood torrent. Breast cancer (BC) is a cancer type that originates mainly in milk glands and ducts of the breast; however, it can also metastasise from the breast to other areas of the body. Various factors, such as smoking, physical activity, obesity, alcohol, and poor nutrition, contribute to the development of this condition. In addition, genetic alterations, such as gene mutations and chromosomal abnormalities, result in the loss of function of tumour suppressor genes (TSG) or increased oncogenes (OG) activity/oncogenes activation. Currently, cancer is associated with an aberrant epigenetic regulation that modifies both OG activation and TSG silencing. The discipline of epigenetics focuses on studying modifications, such as DNA methylation, differential histone modifications, and micro-RNA at promoter sites during gene expression. For example, aberrant methylations could be associated with BC development, wherein some biocompounds, including polyphenols, have shown effects as chemopreventive agents. However, it remains unclear if biocompounds can induce epigenetic changes or regulate other metabolic pathways. The present chapter offers an overview of the epigenetic regulation effect of polyphenols on breast cancer.

Epigenetic Mechanisms Involved in the Effects of Maternal Hyperhomocysteinemia on the Functional State of Placenta and Nervous System Plasticity in the Offspring

According to modern view, susceptibility to diseases, specifically to cognitive and neuropsychiatric disorders, can form during embryonic development. Adverse factors affecting mother during the pregnancy increase the risk of developing pathologies. Despite the association between elevated maternal blood homocysteine (Hcy) and fetal brain impairments, as well as cognitive deficits in the offspring, the role of brain plasticity in the development of these pathologies remains poorly studied. Here, we review the data on the negative impact of hyperhomocysteinemia (HHcy) on the neural plasticity, in particular, its possible influence on the offspring brain plasticity through epigenetic mechanisms, such as changes in intracellular methylation potential, activity of DNA methyltransferases, DNA methylation, histone modifications, and microRNA expression in brain cells. Since placenta plays a key role in the transport of nutrients and transmission of signals from mother to fetus, its dysfunction due to aberrant epigenetic regulation can affect the development of fetal CNS. The review also presents the data on the impact of maternal HHcy on the epigenetic regulation in the placenta. The data presented in the review are not only interesting from purely scientific point of view, but can help in understanding the role of HHcy and epigenetic mechanisms in the pathogenesis of diseases, such as pregnancy pathologies resulting in the delayed development of fetal brain, cognitive impairments in the offspring during childhood, and neuropsychiatric and neurodegenerative disorders later in life, as well as in the search for approaches for their prevention using neuroprotectors.

Epigenetic Regulation in Breast Cancer: Insights on Epidrugs.

Breast cancer remains a common cause of cancer-related death in women. Therefore, further studies are necessary for the comprehension of breast cancer and the revolution of breast cancer treatment. Cancer is a heterogeneous disease that results from epigenetic alterations in normal cells. Aberrant epigenetic regulation is strongly associated with the development of breast cancer. Current therapeutic approaches target epigenetic alterations rather than genetic mutations due to their reversibility. The formation and maintenance of epigenetic changes depend on specific enzymes, including DNA methyltransferases and histone deacetylases, which are promising targets for epigenetic-based therapy. Epidrugs target different epigenetic alterations, including DNA methylation, histone acetylation, and histone methylation, which can restore normal cellular memory in cancerous diseases. Epigenetic-targeted therapy using epidrugs has anti-tumor effects on malignancies, including breast cancer. This review focuses on the importance of epigenetic regulation and the clinical implications of epidrugs in breast cancer.

A Computational Approach to Predict the Role of Genetic Alterations in Methyltransferase Histones Genes With Implications in Liver Cancer.

Histone methyltransferases (HMTs) comprise a subclass of epigenetic regulators. Dysregulation of these enzymes results in aberrant epigenetic regulation, commonly observed in various tumor types, including hepatocellular adenocarcinoma (HCC). Probably, these epigenetic changes could lead to tumorigenesis processes. To predict how histone methyltransferase genes and their genetic alterations (somatic mutations, somatic copy number alterations, and gene expression changes) are involved in hepatocellular adenocarcinoma processes, we performed an integrated computational analysis of genetic alterations in 50 HMT genes present in hepatocellular adenocarcinoma. Biological data were obtained through the public repository with 360 samples from patients with hepatocellular carcinoma. Through these biological data, we identified 10 HMT genes (SETDB1, ASH1L, SMYD2, SMYD3, EHMT2, SETD3, PRDM14, PRDM16, KMT2C, and NSD3) with a significant genetic alteration rate (14%) within 360 samples. Of these 10 HMT genes, KMT2C and ASH1L have the highest mutation rate in HCC samples, 5.6% and 2.8%, respectively. Regarding somatic copy number alteration, ASH1L and SETDB1 are amplified in several samples, while SETD3, PRDM14, and NSD3 showed a high rate of large deletion. Finally, SETDB1, SETD3, PRDM14, and NSD3 could play an important role in the progression of hepatocellular adenocarcinoma since alterations in these genes lead to a decrease in patient survival, unlike patients who present these genes without genetic alterations. Our computational analysis provides new insights that help to understand how HMTs are associated with hepatocellular carcinoma, as well as provide a basis for future experimental investigations using HMTs as genetic targets against hepatocellular carcinoma.

Aberrant epigenetic regulation of estrogen and progesterone signaling at the level of endometrial/endometriotic tissue in the pathomechanism of endometriosis.

Endometriosis is a term referring to a condition whereby the endometrial tissue is found outside the uterine cavity. This progressive and debilitating condition affects up to 15% of women of reproductive age. Due to the fact that endometriosis cells may express estrogen receptors (ERα, Erβ, GPER) and progesterone (P4) receptors (PR-A, PR-B), their growth, cyclic proliferation, and breakdown are similar to the processes occurring in the endometrium. The underlying etiology and pathogenesis of endometriosis are still not fully explained. The retrograde transport of viable menstrual endometrial cells with the retained ability to attach within the pelvic cavity, proliferate, differentiate and invade into the surrounding tissue explains the most widely accepted implantation theory. Endometrial stromal cells (EnSCs) with clonogenic potential constitute the most abundant population of cells within endometrium that resemble the properties of mesenchymal stem cells (MSCs). Accordingly, formation of the endometriotic foci in endometriosis may be due to a kind of EnSCs dysfunction. Increasing evidence indicates the underestimated role of epigenetic mechanisms in the pathogenesis of endometriosis. Hormone-mediated epigenetic modifications of the genome in EnSCs or even MSCs were attributed an important role in the etiopathogenesis of endometriosis. The roles of excess estrogen exposure and P4 resistance were also found to be crucial in the development of epigenetic homeostasis failure. Therefore, the aim of this review was to consolidate the current knowledge regarding the epigenetic background of EnSCs and MSCs and the changed properties due to estrogen/P4 imbalances in the context of the etiopathogenesis of endometriosis.

Epigenetic Mechanisms Underlying Melanoma Resistance to Immune and Targeted Therapies.

Melanoma is an aggressive skin cancer reliant on early detection for high likelihood of successful treatment. Solar UV exposure transforms melanocytes into highly mutated tumor cells that metastasize to the liver, lungs, and brain. Even upon resection of the primary tumor, almost thirty percent of patients succumb to melanoma within twenty years. Identification of key melanoma genetic drivers led to the development of pharmacological BRAFV600E and MEK inhibitors, significantly improving metastatic patient outcomes over traditional cytotoxic chemotherapy or pioneering IFN-α and IL-2 immune therapies. Checkpoint blockade inhibitors releasing the immunosuppressive effects of CTLA-4 or PD-1 proved to be even more effective and are the standard first-line treatment. Despite these major improvements, durable responses to immunotherapy and targeted therapy have been hindered by intrinsic or acquired resistance. In addition to gained or selected genetic alterations, cellular plasticity conferred by epigenetic reprogramming is emerging as a driver of therapy resistance. Epigenetic regulation of chromatin accessibility drives gene expression and establishes distinct transcriptional cell states. Here we review how aberrant chromatin, transcriptional, and epigenetic regulation contribute to therapy resistance and discuss how targeting these programs sensitizes melanoma cells to immune and targeted therapies.

Lupus, DNA Methylation, and Air Pollution: A Malicious Triad.

The pathogenesis of systemic lupus erythematosus (SLE) remains elusive to this day; however, genetic, epigenetic, and environmental factors have been implicated to be involved in disease pathogenesis. Recently, it was demonstrated that in systemic lupus erythematosus (SLE) patients, interferon-regulated genes are hypomethylated in naïve CD4+ T cells, CD19+ B lymphocytes, and CD14+ monocytes. This suggests that interferon-regulated genes may have been epigenetically poised in SLE patients for rapid expression upon stimulation by different environmental factors. Additionally, environmental studies have identified DNA (hypo)methylation changes as a potential mechanism of environmentally induced health effects in utero, during childhood and in adults. Finally, epidemiologic studies have firmly established air pollution as a crucial SLE risk factor, as studies showed an association between fine particulate matter (PM2.5) and traditional SLE biomarkers related to disease flare, hospital admissions, and an increased SLEDAI score. In this review, the relationship between aberrant epigenetic regulation, the environment, and the development of SLE will be discussed.

Polyphenols as Potent Epigenetics Agents for Cancer.

Human diseases such as cancer can be caused by aberrant epigenetic regulation. Polyphenols play a major role in mammalian epigenome regulation through mechanisms and proteins that remodel chromatin. In fruits, seeds, and vegetables, as well as food supplements, polyphenols are found. Compounds such as these ones are powerful anticancer agents and antioxidants. Gallic acid, kaempferol, curcumin, quercetin, and resveratrol, among others, have potent anti-tumor effects by helping reverse epigenetic changes associated with oncogene activation and tumor suppressor gene inactivation. The role dietary polyphenols plays in restoring epigenetic alterations in cancer cells with a particular focus on DNA methylation and histone modifications was summarized. We also discussed how these natural compounds modulate gene expression at the epigenetic level and described their molecular targets in cancer. It highlights the potential of polyphenols as an alternative therapeutic approach in cancer since they modulate epigenetic activity.

Astronauts Plasma-Derived Exosomes Induced Aberrant EZH2-Mediated H3K27me3 Epigenetic Regulation of the Vitamin D Receptor.

There are unique stressors in the spaceflight environment. Exposure to such stressors may be associated with adverse effects on astronauts' health, including increased cancer and cardiovascular disease risks. Small extracellular vesicles (sEVs, i.e., exosomes) play a vital role in intercellular communication and regulate various biological processes contributing to their role in disease pathogenesis. To assess whether spaceflight alters sEVs transcriptome profile, sEVs were isolated from the blood plasma of 3 astronauts at two different time points: 10 days before launch (L-10) and 3 days after return (R+3) from the Shuttle mission. AC16 cells (human cardiomyocyte cell line) were treated with L-10 and R+3 astronauts-derived exosomes for 24 h. Total RNA was isolated and analyzed for gene expression profiling using Affymetrix microarrays. Enrichment analysis was performed using Enrichr. Transcription factor (TF) enrichment analysis using the ENCODE/ChEA Consensus TF database identified gene sets related to the polycomb repressive complex 2 (PRC2) and Vitamin D receptor (VDR) in AC16 cells treated with R+3 compared to cells treated with L-10 astronauts-derived exosomes. Further analysis of the histone modifications using datasets from the Roadmap Epigenomics Project confirmed enrichment in gene sets related to the H3K27me3 repressive mark. Interestingly, analysis of previously published H3K27me3–chromatin immunoprecipitation sequencing (ChIP-Seq) ENCODE datasets showed enrichment of H3K27me3 in the VDR promoter. Collectively, our results suggest that astronaut-derived sEVs may epigenetically repress the expression of the VDR in human adult cardiomyocytes by promoting the activation of the PRC2 complex and H3K27me3 levels.

Epigenetic Regulation of Chondrocytes and Subchondral Bone in Osteoarthritis.

The aim of this review is to provide an updated review of the epigenetic factors involved in the onset and development of osteoarthritis (OA). OA is a prevalent degenerative joint disease characterized by chronic inflammation, ectopic bone formation within the joint, and physical and proteolytic cartilage degradation which result in chronic pain and loss of mobility. At present, no disease-modifying therapeutics exist for the prevention or treatment of the disease. Research has identified several OA risk factors including mechanical stressors, physical activity, obesity, traumatic joint injury, genetic predisposition, and age. Recently, there has been increased interest in identifying epigenetic factors involved in the pathogenesis of OA. In this review, we detail several of these epigenetic modifications with known functions in the onset and progression of the disease. We also review current therapeutics targeting aberrant epigenetic regulation as potential options for preventive or therapeutic treatment.

Aberrant epigenetic regulation of RARβ by TET2 is involved in cutaneous squamous cell carcinoma resistance to retinoic acid

With the growing incidence of cutaneous squamous cell carcinoma (CSCC), the treatment-resistant invasive CSCC should be taken seriously. Retinoic acid receptor β (RARβ) functions as a tumor suppressor gene and is associated with the proliferation inhibition to retinoic acid. Demethylase TET2 directed epigenetic landscape contributes to cell malignant transform and is involved in therapeutic resistance in tumors. Whether aberrant TET2 participated in the deficient RARβ remains largely unknown. Hereby, we identified the aberrant-TET2 directed epigenetic landscape contribute to the deficient RARβ in CSCC. The immunohistochemistry was used to detect the expression of RARβ and TET2. The bisulfite sequencing PCR was used to detect the RARβ promoter methylation. Plasmid transfection was used to upregulate TET2 in CSCC cells. Stable overxpressed TET2 cells were used to detect the effect of TET2 on RARβ and drug sensitivity in the CCSC. We observed RARβ decreased with promoter hypermethylation in CSCC and aberrant TET2 associated with deficient RARβ. We upregulated TET2 could reverse promoter hypermethylation and showed a significantly increased expression of RARβ, which enhanced the sensitivity of tumor cells to retinoic acid treatment. Aberrant TET2 leaded to the hypermethylation of RARβ promoter, which contributed to the deficient RARβ in CSCC. While reversing the hypermethylation of the RARβ promoter by recovering the TET2 could enhance tumor cells to be sensitive to retinoic acid.