Search Results (35)

Central chondrosarcoma is the second most common primary malignant bone tumour, and grade progression markedly worsens prognosis. The contributions of lipid metabolic reprogramming and epigenetic co-dysregulation to grade progression remain poorly characterised. We integrated a bulk RNA-seq discovery cohort of 53 graded central chondrosarcomas (GSE299759) with a single-cell analysis of eight chondrosarcomas (GSE184118). Because the atypical cartilaginous tumour (ACT) and dedifferentiated groups each comprised only three samples, the Grade 3 versus Grade 2 contrast was pre-specified as the primary comparison. Curated panels of 44 lipid metabolism genes and 50 epigenetic regulators were assessed by differential expression and a correlation-based connectivity ranking, evaluated by permutation testing. In the primary Grade 3 versus Grade 2 comparison, SQLE, ACACA, and FASN were upregulated (FDR < 0.05), indicating a grade-associated increase in de novo lipogenesis. In the exploratory Grade 3 versus ACT comparison, additional lipid genes (HMGCR, LDLRAP1) and the epigenetic regulators EHMT2 and SIRT2 showed altered expression, although the small ACT group limits these estimates. A connectivity ranking highlighted FASN, KMT2C, TET2, SETD5, and KDM5B; permutation testing confirmed this co-expression structure was non-random (p < 0.0001). Single-cell analysis showed FASN, SETD5, and KDM5B are expressed predominantly in malignant cells, whereas KMT2C and TET2 are not, indicating cell-type heterogeneity. De novo lipogenesis upregulation is the most consistent lipid alteration in high-grade central chondrosarcoma, nominating SQLE, ACACA, and FASN as candidates for experimental investigation. Full article

Background/Objectives: Observational studies have reported comorbidity between diabetic retinopathy (DR) and physical frailty, but their genetic interplay remains incompletely understood. This study evaluated shared genetic architecture and potential causal relationships between DR severity and frailty-related phenotypes (FRPs). Methods: GWAS summary statistics were analyzed for four DR phenotypes (broad DR, background DR [BDR], severe non-proliferative DR, and proliferative DR [PDR]) and six FRPs, including frailty index (FI), appendicular lean mass, handgrip strength (HGS), and walking pace (UWP). Global and local genetic correlations were estimated using LDSC, HDL, and LAVA. Causality was assessed using bidirectional Mendelian randomization (MR) and latent causal variable (LCV) analyses. Biological mechanisms were investigated using partitioned heritability, cross-trait meta-analysis, Bayesian colocalization, tissue and cell enrichment, prioritization (MAGMA/TWAS), and 3D chromatin annotation. Results: BDR and PDR showed positive genetic correlations with FI and negative correlations with UWP. Local genetic correlation analyses identified 82 significant regions, including signals on chromosome 6. MR supported a directional effect in which genetic liability to DR was associated with higher FI and lower HGS, with no evidence of reverse causation. LCV indicated partial genetic causality within a shared polygenic architecture. Cross-trait meta-analysis and colocalization highlighted the MHC region, prioritizing C2, AIF1, NOTCH4, and EHMT2. Additional non-MHC loci included the BCL2L15 gene cluster and TERF1. Conclusions: DR and frailty share genetic determinants involving neurovascular, metabolic, and immune-inflammatory pathways, supporting an association between DR liability and frailty-related decline. Future longitudinal and functional studies are needed to validate these findings and assess candidate pleiotropic genes. Full article

Polystyrene nanoplastics (PS-NPs) are emerging environmental contaminants increasingly linked to male reproductive toxicity; however, the molecular mechanisms underlying testicular damage remain unclear. This study evaluated PS-NP-associated testicular damage in rats after 55 days of exposure and assessed the modulatory effects of Nelumbo nucifera leaf, flower, and rhizome extracts, with quercetin as a reference. PS-NP exposure reduced spermatogenic cell populations, testicular, epididymal weights, and sperm motility. These changes were accompanied by increased NOX4 and NF-κB expression, upregulation of intrinsic apoptosis-related genes (Tp53, Bax, Caspase-9, and Caspase-3), elevated caspase-3 and caspase-9 protein levels, and enhanced cleaved caspase-3 immunoreactivity. In contrast, Fas and Caspase-8 were downregulated, confirming intrinsic mitochondrial apoptosis. PS-NP exposure also altered reproductive hormone receptor expression (LHr, FSHr, and AR) and dysregulated chromatin-regulatory genes, with increased Dnmt1, Dnmt3a, and Ehmt2 (G9a) and decreased Hdac1 and Ep300. Co-administration of N. nucifera attenuated most of these alterations, with the rhizome extract exhibiting the most pronounced protective effect. GO and PPI network analyses suggested functional connectivity among stress-responsive, apoptotic, and chromatin-modifying proteins. Docking simulations indicated phytochemical-apoptosis-related protein interactions. PS-NPs may impair testicular homeostasis through coordinated stress, apoptosis, endocrine disturbance, and epigenetic dysregulation, with possible relevance to male reproductive health, while N. nucifera shows promise as a protective modulator. Full article

Background: EHMT2 (G9a) is a key epigenetic regulator frequently overexpressed in various cancers. While several inhibitors exist, their in vivo efficacy and pharmacokinetic (PK) properties remain poorly characterized. Methods: We compared the biochemical, cellular, and PK profiles of two widely used EHMT2 inhibitors, BIX-01294 and UNC0642, and evaluated their antitumor efficacy in xenograft and syngeneic mouse models. Results: Despite a higher enzymatic potency of UNC0642 (IC₅₀ = 0.277 μM) compared to BIX-01294 (IC₅₀ = 1.983 μM), BIX-01294 demonstrated superior cellular growth inhibition and higher intracellular accumulation. PK analysis further revealed that BIX-01294 achieved higher systemic exposure (AUC) and a wider therapeutic window via intraperitoneal administration, whereas UNC0642 exhibited dose-limiting lethality above 8 mg/kg. In HT-29 and MIA PaCa-2 xenografts, BIX-01294 (40 mg/kg) achieved up to 70.6% tumor growth inhibition (TGI), substantially surpassing UNC0642. Furthermore, in MC38 syngeneic models, a BIX-01294/anti-PD-L1 antibody combination produced an additive effect. This combination markedly increased the number of tumor-infiltrating CD8α⁺ T cells and NK1.1⁺ cells. Conclusions: These results suggest that BIX-01294 is more effective in vivo than UNC0642 due to its favorable PK profile and superior cellular uptake. Our findings support the further development of EHMT2 inhibitors as potent partners for immune checkpoint blockades. Full article

Background: Kleefstra syndrome (KS) is a rare neurodevelopmental disorder caused by haploinsufficiency of EHMT1; it is characterized by global developmental delay, intellectual disability, hypotonia, distinctive facial features, and variable congenital anomalies. Autistic features, behavioral abnormalities and severe speech impairment are frequently reported. However, molecularly confirmed cases of KS from Africa remain extremely limited, largely due to restricted access to genomic diagnostic infrastructures. Methods: We describe a 15-month-old patient from Rwanda presenting with neonatal hypotonia, global developmental delay, short stature, and characteristic dysmorphic facial features. Comprehensive clinical evaluation was performed, followed by trio-based exome sequencing to identify the underlying genetic cause of this neurodevelopmental disorder. Results: Exome sequencing identified a de novo heterozygous frameshift variant in EHMT1 (NM_024757.5: c.2871dup; p. Phe958Leufs*219), confirming the diagnosis of KS. Conclusions: This report presents the first molecularly confirmed case of KS in Rwanda. It highlights additional clinical features like bilateral 5th toe clinodactyly, short stature and absence of obesity in KS. There is a need to further delineate the study of EHMT1 and investigate the natural history of KS across different populations for optimal patient management and to reduce diagnostic odyssey. The diagnostic utility of exome sequencing for neurodevelopmental disorders needs to be strengthened, with strong emphasis on expanding genomic medicine to help diagnose rare diseases in resource-limited settings. Full article

Background and Objectives: There is adherence to a healthy Mediterranean diet (MedDiet), but adherence varies widely. Precision nutrition is increasingly interested in individual characteristics influencing diet adherence, but few studies have examined personality traits. Our main aim was to investigate the association between personality traits and MedDiet adherence. Our secondary aims were to explore genome-wide genetic variants associated with neuroticism, including replication of previous findings, as well as to explore gene–MedDiet interactions. Methods: We analyzed participants (aged 55–75) in the PREDIMED-Plus-Valencia study and measured clinical, lifestyle, and genetic factors. The Eysenck Personality Questionnaire-Revised (EPQ-R) was used to measure neuroticism, psychoticism, and extraversion. Genotyping was undertaken, and associations with candidate SNPs, genome-wide association studies (GWAS), genetic risk scores (GRS), and gene–MedDiet interactions were explored. Results: Neuroticism was inversely (beta = −0.09; p = 0.001) associated with adherence to the Mediterranean diet (MEDAS-17). Likewise, the probability of low MedDiet adherence increased neuroticism (OR: 1.27; 95% CI: 1.02–1.60; p = 0.031 per SD). In the GWAS for this trait, several SNPs surpassed the suggestive level of statistical significance. The most strongly associated was rs10181407-NDUFA10 (NADH dehydrogenase 1 alpha subcomplex subunit 10) (beta = −2.39; p = 2.70 × 10⁻⁶). The GRS for neuroticism was significantly associated with MedDiet adherence (beta = −0.18; p = 0.020), increasing the causality level. We replicated some candidate SNPs, and among them, the rs2243873-EHMT2 (euchromatic histone lysine methyltransferase 2) gene. The analysis of gene–MedDiet interactions revealed the role of these dietary modulations. Conclusions: Neuroticism was the personality trait most inversely associated with MedDiet adherence, suggesting its integration in precision nutrition analysis. Moreover, neuroticism-related genetics and MedDiet modulations will also be important. Full article

JC virus (JCV) replicates within the nuclei of glial cells in the human brain and causes progressive multifocal leukoencephalopathy. JCV possesses a small, circular, double-stranded DNA genome, divided into early and late protein-coding regions. The non-coding control region (NCCR) functions bidirectionally for both early and late genes, and the agnogene is located downstream of TCR and upstream of three capsid proteins in the late region. Previously, in cell culture systems, we demonstrated that these capsid proteins accumulate in intranuclear domains known as promyelocytic leukemia nuclear bodies (PML-NBs), where they assemble into virus-like particles (VLPs). To investigate the agnogene’s function, VLPs were formed in its presence or absence, and differential gene expression was analyzed using microarray technology. The results revealed altered expression of histone-modifying enzymes, including methyltransferases (EHMT1, PRMT7) and demethylases (KDM2B, KDM5C, KDM6B), as well as various kinases and phosphatases. Notably, CTDP1, which dephosphorylates the C-terminal domain of an RNA polymerase II subunit, was also differentially expressed. The changes were predominant in the presence of the agnogene. These findings indicate that the agnogene and/or its protein product likely influence epigenetic regulation associated with PML-NBs, which may influence cell cycle control. Consistently, in human brain tissue, JCV-infected glial cells displayed maintenance of a diploid chromosomal complement, likely through G2 arrest. The precise mechanism of this, however, remains to be elucidated. Full article

Psoriasis involves complex epigenetic alterations, but detailed studies on histone methyltransferases and their role in disease progression are limited. We conducted a comprehensive analysis of nearly 300 transcriptomes, focusing mainly on differential expression of protein isoform-coding transcripts within the SET domain family of histone methyltransferases. Consistent with previous findings, EZH2 transcripts showed increased expression in lesional skin, indicating altered H3K27 methylation that may enhance gene silencing, promoting keratinocyte proliferation and inflammatory responses. In the SET2 family, ASH1L exhibited reversed expression patterns between non-lesional and lesional skin, while NSD1 and NSD2 were upregulated, and SETD2 downregulated in lesions, suggesting disrupted H3K36 methylation that may affect immune responses and keratinocyte proliferation. Among H3K9 methyltransferases, SUV39 members, SUV39H2 was upregulated in lesions, whereas EHMT1 transcripts increased in non-lesional skin, and SETDB2 decreased in lesions. Additionally, PRDM family members such as PRDM2, MECOM (PRDM3), PRDM6, and PRDM8 showed altered expression in lesional skin. The H4K20 methylating SUV4-20 subfamily member, a SUV420H1 transcript, and SETD8 belonging to the other SET domain-containing family of methyltransferases were significantly increased in non-lesional skin and in lesions, respectively. Overall, aberrant expression and isoform variability of histone methyltransferases likely contribute to psoriasis pathogenesis by dysregulating proliferation, differentiation, and immune responses. Full article

Kleefstra syndrome (KS) is a rare neurodevelopmental disorder associated with disruptions in the EHMT1 gene, often leading to intellectual disability, autism spectrum behaviors and epilepsy. The electroencephalogram (EEG) serves as a non-invasive tool to explore brain function in KS; yet, systematic characterizations of EEG features remain extremely limited. This review synthesizes current evidence on EEG findings in KS, highlighting the high prevalence of nonspecific abnormalities and seizures, but the absence of a consistent electrophysiological biomarker. Given the growing role of machine learning (ML) in extracting patterns from EEG data in related disorders—such as Angelman, Rett and Fragile X syndromes—this review explores how similar approaches could be adapted for KS. Despite promising perspectives, a lack of large-scale, publicly available EEG datasets hinders the application of ML methodologies in KS research. Future directions are proposed to address these gaps, including standardized EEG data collection, adoption of quantitative EEG analyses and integration of ML techniques adapted for small datasets. This multidisciplinary strategy holds potential for improving early diagnosis, monitoring and personalized interventions in Kleefstra syndrome. Full article

Background: Kleefstra syndrome 1(KLEFS1, OMIM#610253) is a rare neurodevelopmental disorder (NDD) instigated by heterozygous variants or microdeletions occurring in the 9q34.4 genomic region of the euchromatic histone methyltransferase-1 (EHMT1) gene and is inherited in an autosomal dominant (AD) manner. The clinical phenotype of KLEFS1 includes moderate to severe intellectual disability (ID), hypotonia, and distinctive facial features and additionally involves other organ systems (heart, renal, genitourinary, sensory) albeit with phenotypic heterogeneity between patients. The purpose of this study is to expand the genotypic spectrum of KLEFS1 and compare phenotypic features of the syndrome of already published cases. Methods: Exome sequencing (ES), chromosomal microarray analysis (CMA), as well as sanger sequencing, for confirmation of the de novo status of the frameshift variant, were used. Results: Here we describe two more cases, both males with a similar age and carriers of novel variants; one with a frameshift variant involving exon 13: p.Val692Glyfs*64 and the other with the smallest so far described, 11 Kb (exons 19-25), 9q34.4 microdeletion: 9q34.3 (140703393-140714454). Both presented with an NDD disorder with one showing more severe ID with significant social disabilities, while the other with the microdeletion had mild ID and following a normal education curriculum. Neither of them were obese nor had any other significant organ system disorder. Conclusions: The observed phenotypic variability due to genotypic differences in the two children contributes to the expanding spectrum of KLEFS1 disease phenotypes. Full article

The epigenetic regulation of gene expression through the covalent modification of histones is crucial for developing germline cells. To study the regulatory role of alternative splicing (AS) of euchromatic histone lysine methyltransferase 2 (EHMT2/G9A) in spermatogenesis in Mongolian horses, this study first examines the localization of the EHMT2 gene in testicular support cells and then predicts the higher-order structures of sequences with and without AS. Two types of lentiviral vectors for overexpression were subsequently constructed for the EHMT2 gene, one with AS and one without, to infect support cells. The proliferation and activity of infected cells were measured using CCK8, and the differential expression of spermatogenesis-related genes in the two types of support cells was analyzed via qRT–PCR. We analyzed the expression of EHMT2 by immunofluorescence staining. EHMT2 was expressed in the nuclei of Sertoli cells. The expression of spermatogenesis-related genes was measured in the two types of cells. The results reveal that the expression levels of the FSH, Stra8, CCNB2, CDC27, NRG1, PPP2R5C, CCNB2, and YWHAZ genes in the AS group were greater than those in the control group. These results indicate that AS events in EHMT2 affect gene expression and thus affect spermatogenesis. Full article

Background/objectives: Euchromatic histone lysine methyltransferase 2 (EHMT2, also known as G9a) is a mammalian histone methyltransferase that catalyzes the dimethylation of histone 3 lysine 9 (H3K9). On human chromosome 15, the parental-specific expression of Prader–Willi Syndrome (PWS)-related genes, such as SNRPN and SNORD116, are regulated through the genetic imprinting of the PWS imprinting center (PWS-IC). On the paternal allele, PWS genes are expressed whereas the epigenetic maternal silencing of PWS genes is controlled by the EHMT2-mediated methylation of H3K9 in PWS-IC. Here, we measured the effects of RNA interference of EHMT2 on the maternal expression of genes deficient in PWS in mouse model and patient iPSC-derived cells. Methods: We used small interfering RNA (siRNA) oligonucleotides and lentiviral short harpin RNA (shRNA) to reduce Ehtm2/EHMT2 expression in mouse Snord116 deletion primary neurons, PWS patient-derived induced pluripotent stem cell (iPSC) line and PWS iPSC-derived neurons. We then measured the expression of transcript or protein (if relevant) of PWS genes normally silenced on the maternal allele. Results: With an approximate reduction of 90% in EHMT2 mRNA and more than 80% of the EHMT2 protein, we demonstrated close to a 2-fold increase in the expression of maternal transcripts for SNRPN and SNORD116 in PWS iPSCs treated with siEHMT2 compared to PWS iPSC siControl. A similar increase in SNORD116 and SNRPN RNA expression was observed in PWS iPSC-derived neurons treated with shEHMT2. Conclusions: RNAi reduction in EHMT2 activates maternally silenced PWS genes. Further studies are needed to determine whether the increase is therapeutically relevant. This study confirms the role of EHMT2 in the epigenetic regulation of PWS genes. Full article

G9a, also named EHMT2, is a histone 3 lysine 9 (H3K9) methyltransferase responsible for catalyzing H3K9 mono- and dimethylation (H3K9me1 and H3K9me2). G9a contributes to various aspects of embryonic development and tissue differentiation through epigenetic regulation. Furthermore, the aberrant expression of G9a is frequently observed in various tumors, particularly in prostate cancer, where it contributes to cancer pathogenesis and progression. This review highlights the critical role of G9a in multiple cancer-related processes, such as epigenetic dysregulation, tumor suppressor gene silencing, cancer lineage plasticity, hypoxia adaption, and cancer progression. Despite the increased research on G9a in prostate cancer, there are still significant gaps, particularly in understanding its interactions within the tumor microenvironment and its broader epigenetic effects. Furthermore, this review discusses the recent advancements in G9a inhibitors, including the development of dual-target inhibitors that target G9a along with other epigenetic factors such as EZH2 and HDAC. It aims to bring together the existing knowledge, identify gaps in the current research, and suggest future directions for research and treatment strategies. Full article

Prostate cancer is the most common cancer and the second leading cause of cancer deaths among men in the USA. Several studies have demonstrated the antitumor properties of saffron in different types of cancers, including prostate cancer. The oral administration of saffron extract has been reported to have antitumor effects on aggressive prostate-cancer-cell-line-derived xenografts in nude male mice. The objective of this study was to carry out in vitro studies of saffron-treated prostate cancer cells to ascertain the effects of saffron on key intermediates in prostate carcinogenesis. Our studies demonstrated the significant inhibition of cell proliferation for androgen-sensitive prostate cancer cell lines via apoptotic pathways. We also demonstrate the statistically significant down-regulation of DNA methyltransferases (COMT, MGMT, EHMT2, and SIRT1 deacetylase) in saffron-treated prostate cancer cells. In addition, saffron-treated prostate cancer cells displayed a statistically significant dysregulation of DNA repair intermediates (WRN, p53, RECQ5, MST1R, and WDR70) in a time-dependent manner. Furthermore, Western blot analysis demonstrated that saffron treatment induced changes in the expression of other key genes (DNMT1, DNMT3b, MBD2, CD44, HDAC3, c-Myc, NF-kB, TNFα, AR, N-RAS, and PTEN) in prostate cancer cells. Collectively, our findings demonstrate the important mechanisms by which saffron mediates anti-tumor properties in prostate cancer. These findings suggest that the use of saffron supplements alongside standard treatment protocols may yield beneficial effects for individuals with prostate cancer. Full article

A decreased hemoglobin synthesis is contemplated as a pathological indication of β-thalassemia. Recent studies show that EPZ035544 from Epizyme could induce fetal hemoglobin (HbF) levels due to its proven capability to inhibit euchromatin histone lysine methyl transferase (EHMT2). Therefore, the development of EHMT2 inhibitors is considered promising in managing β-thalassemia. Our strategy to find novel compounds that are EHMT2 inhibitors relies on the virtual screening of ligands that have a structural similarity to N2-[4-methoxy-3-(2,3,4,7-tetrahydro-1H-azepin-5-yl) phenyl]-N4,6-dimethyl-pyrimidine-2,4-diamine (F80) using the PubChem database. In silico docking studies using Autodock Vina were employed to screen a library of 985 compounds and evaluate their binding ability with EHMT2. The selection of hit compounds was based on the docking score and mode of interaction with the protein. The top two ranked compounds were selected for further investigations, including pharmacokinetic properties analysis and molecular dynamics simulations (MDS). Based on the obtained docking score and interaction analysis, N-(4-methoxy-3-methylphenyl)-4,6-diphenylpyrimidin-2-amine (TP1) and 2-N-[4-methoxy-3-(5-methoxy-3H-indol-2-yl)phenyl]-4-N,6-dimethylpyrimidine-2,4-diamine (TP2) were found to be promising candidates, and TP1 exhibited better stability in the MDS study compared to TP2. In summary, our approach helps identify potential EHMT2 inhibitors, and further validation using in vitro and in vivo experiments could certainly enable this molecule to be used as a therapeutic drug in managing β-thalassemia disease. Full article