Search Results (199)

Quaternary ammonium compounds (QACs) are a class of chemicals used for their antimicrobial, surfactant, and antistatic properties. QACs are present in many consumer products, and people are regularly exposed to them. We have previously shown reproductive toxicity in mice exposed to the disinfectants alkyl dimethyl benzyl ammonium chloride (ADBAC) and dodecyl dimethyl ammonium chloride (DDAC). To assess the long-term reproductive impacts, a generational reproductive study was conducted. Sperm parameters were determined by CASA and epigenetic enzyme mRNA expression was determined by pathway-focused RT-PCR. Mice ambiently exposed to ADBAC+DDAC exhibited decreases in reproductive indices that persisted through the F1 generation. Male mice (F0) dosed with 120 mg/kg/day of ADBAC+DDAC exhibited decreased sperm concentration and motility that persisted through the F1 generation. Changes in the mRNA expression of chromatin-modifying enzymes in the testes were seen. Two histone acetyltransferases (Hat1 and Kat2b) were upregulated, and one lysine-specific demethylase (Kdm6b) was downregulated in the F0 generation. The DNA methyltransferase Dnmt1 was downregulated in F1 males. These changes in chromatin-modifying enzymes are known to decrease fertility and could be a mechanism for ADBAC+DDAC reproductive toxicity. In all experiments, the F2 generation was similar to the controls, showing multi-generational but not trans-generational epigenetic inheritance. Full article

Conventional immediate and high-temperature immediate acid treatment are crucial techniques for breaking the diapause state of silkworm eggs, but their molecular mechanisms remain unclear. This study prepared diapause eggs (CK), conventional immediate acid-treated eggs (46 °C, 5 min, and CG), and high-temperature immediate acid-treated eggs (47.5 °C, 7 min, and GW) and analyzed the transcriptome and metabolome to screen for key expressed genes and key metabolites. Transcriptome results showed that 688, 823, and 222 differentially expressed genes (DEGs) were obtained from CK vs. CG, CK vs. GW, and CG vs. GW, respectively, and 12 DEGs significantly upregulated in all three comparisons (CK vs. CG, CK vs. GW, and CG vs. GW), including glycine-N-methyltransferase, choline dehydrogenase, Hsp68, and Hsp70. The LC-MS analysis results showed that 854, 711, and 506 differential metabolites (DMs) were obtained from CK vs. CG, CK vs. GW, and CG vs. GW, respectively. A total of seven DMs upregulated in all three comparisons and with |log₂Fold Change| ≥ 0.5 in CG vs. GW, including tyrosine-isoleucine-histidine, phenylalanyl-tyrosine, tyrosine-phenylalanine-glutamate-lysine, and histidylleucine, as well as 12 downregulated DMs, were identified. Additionally, it was found that γ-linolenic acid and triglycerides were upregulated in CG vs. GW. The conjoint analysis results revealed that four small peptides, including tyrosine-isoleucine-histidine, phenylalanyl-tyrosine, tyrosine-phenylalanine-glutamate-lysine, and histidylleucine, exhibited a highly significant positive correlation with Hsp70 family genes such as Hsp68 and Hsp70. This suggests that these small peptides, along with γ-linolenic acid and triglycerides, may play a crucial role in the resistance of silkworm eggs to high-temperature stress and the associated oxidative stress. Full article

The Complex Proteins Associated with Set1 (COMPASS)-like complex regulates developmental gene expression via histone 3 lysine 4 (H3K4) methylation and other transcriptional mechanisms. Several members of the lysine methyltransferase 2C and D (KMT2C/D)-COMPASS-like complex are implicated in human congenital heart and vascular defects. The investigation of the orthologous Trithorax-related (Trr)-COMPASS-like complex in Drosophila melanogaster (the fruit fly) offers a versatile model to explore gene function in the developing heart. Previous studies have demonstrated the importance of the genes encoding complex members in the later stages of heart development and heart function in both insect and mammalian models. In this study, we investigate the function of trr and the complex member PAX transcription activation domain interacting protein (Ptip) within the Drosophila embryonic dorsal vessel (heart tube). The loss of activity of either gene results in cardiac cell division defects in the Tinman (Tin) and Seven up (Svp) lineages. Furthermore, genetic interaction studies identify a strong synergistic interaction between Ptip and trr implicating Ptip–Trr–COMPASS-like complex regulation in cardiac progenitor cell division. Interestingly, global H3K4 mono-methylation (H3K4me1) and di-methylation (H3K4me2) levels were not significantly affected in either Ptip or trr mutants, suggesting that these proteins regulate cardiac target genes at a local scale. In conclusion, these results suggest that the Trr/KMT2C/D–COMPASS-like complex is a key regulator of cardiac progenitor cell division during early embryonic heart development. Full article

PR/SET domain 2 (PRDM2)/RIZ is a member of the histone/protein methyltransferases (PRDMs) superfamily. Discovered to have the ability to bind retinoblastoma in the mid-1990s, PRDM2 was assumed to play a role in neuronal development. Like other family members characterized by a conserved N-terminal PR structural domain and a classical C2H2 zinc-finger array at the C-terminus, PRDM2 encodes two major protein types, the RIZ1 and RIZ2 isoforms. The two subtypes differ in the presence or absence of the PR domain: the RIZ1 subtype has the PR domain, whereas the RIZ2 subtype lacks it. The PR domain exhibits varying conservation levels across species and shares structural and functional similarities with the catalytic SET domain, defining histone methyltransferases. Functioning as an SET domain, the PR domain possesses protein-binding interfaces and acts as a lysine methyltransferase. The variable number of classic C2H2 zinc fingers at the C-terminus may mediate protein–protein, protein–RNA, or protein–DNA interactions. An imbalance in the RIZ1/RIZ2 mechanism may be an essential cause of malignant tumors, where PR-positive isoforms are usually lost or downregulated. Conversely, PR-negative isoforms are always present at higher levels in cancer cells. RIZ1 isoforms are also important targets for estradiol interaction with hormone receptors. PRDM2 can regulate gene transcription and expression combined with transcription factors and plays a role in the development of several systemic diseases through mRNA expression deletion, code-shift mutation, chromosomal deletion, and missense mutation occurrence. Thus, PRDM2 is a key indicator for disease diagnosis, but it lacks systematic summaries to serve as a reference for study. Therefore, this paper describes the structure and biological function of PRDM2 from the perspective of its role in various systemic diseases. It also organizes and categorizes its latest research progress to provide a systematic theoretical basis for a more in-depth investigation of the molecular mechanism of PRDM2’s involvement in disease progression and clinical practice. Full article

Histone methylation plays important roles in plant development and adaptation to multiple stresses. SET domain group (SDG) proteins are identified as plant histone lysine methyltransferases in Arabidopsis and other crops. However, the SDG gene family and its functional roles in tomato remain unknown. In this research, 48 tomato SDG (SlSDG) gene family members were identified, and their chromosomal locations and conserved motifs were determined. According to phylogenetic analysis, the SlSDGs are divided into seven groups, which is consistent with Arabidopsis and rice. Promoter analysis indicated that the SlSDGs may be associated with biotic and abiotic stress responses. The expression pattern of SlSDGs illustrates that heat and cold stress significantly influence the transcript abundance of SDG14/19/21/23/48. The results of a VIGS assay showed that silencing SlSDG19 and SlSDG48 decreases tomato heat tolerance, while silencing SlSDG14 improves the heat tolerance of tomato plants. The analysis of downstream regulating genes indicated that heat shock proteins (HSPs), especially HSP70 and HSP90, act as critical effectors. Similarly, the experimental assay and expression analysis suggest that SDG21 and SDG23 positively and negatively regulate tomato cold tolerance through the CBF-COR pathway, respectively. These findings clarify the function of tomato SDG proteins and provide insight for the genetic improvement of tomato for temperature stress tolerance. Full article

Background: SET domain-containing 5 (SETD5) is a member of the protein lysine-methyltransferase family. SETD5 gene mutations cause disorders of the epigenetic machinery which determinate phenotypic overlap characterized by several abnormalities. SEDT5 gene variants have been described in patients with KBG and Cornelia de Lange (CdL) syndromes. Case description: A female patient with severe short stature and intellectual disability had been followed since she was 9 years old. Several causes of short stature were ruled out. At the age of 12 years, her height was 114 cm (−5.22 SDS), weight 19 kg (−5.88 SDS), BMI 14.6 kg/m² (−2.26 SDS), and was Tanner stage 1. The target height for the proband was 151.65 cm (−1.80 SDS). The bone age (BA) was delayed by 3 years compared to chronological age. The growth rate was persistently deficient (<<2 SDS). Physical examination revealed dysmorphic features. Genetic analysis documented a de novo SETD5 gene mutation (c.890_891delTT), responsible for phenotypes in the context of an overlap syndrome between the phenotype of MDR23, CdL and KBG syndromes. Recombinant growth hormone therapy (rhGH) was started at the age of 12 years. After both one year (+3.16 SDS) and two years (+2.9 SDS), the growth rate significantly increased compared with the pre-therapy period. Conclusion: This is the first case of a patient with overlap syndrome due to SETD5 mutation treated with rhGH. The review of the scientific literature highlighted the clinical and molecular features of SETD5 gene mutation and the use of rhGH therapy in patients suffering from CdL and KBG syndromes. Full article

Curcumin-mediated anti-cancer properties have been correlated with the inhibition of oncogenic molecules such as mutp53 and c-Myc. Their targeting is therapeutically significant, as p53, following point mutations, can acquire oncogenic functions, and c-Myc overexpression, due to translocations, point mutations, protein/protein interactions, or epigenetic modifications, plays a central role in cancer cell proliferation and metabolic reprogramming, particularly in colorectal cancer. In a previous study, we showed that curcumin strongly downregulated mutp53 while activating wtp53 and reduced the expression of methyltransferases such as EZH2, G9a, and MLL-1 in colon cancer cells. Based on this background, here we investigated whether the dysregulation of such methyltransferases could correlate with the effect observed on p53. We also explored whether these epigenetic changes could affect c-Myc expression in these cells. By Western blot analysis and RT-qPCR, we found that the downregulation of EZH2; G9a; and, to a lesser extent, KDM1, which was also reduced by curcumin, correlated with the decrease in mutp53 and that the reduction of EZH2 and KDM1 correlated with the activation of wtp53. Regarding c-Myc, we unveiled the occurrence of a positive feedback loop between it and MLL-1, which was inhibited by curcumin, independently of the p53 status. In conclusion, this study provides new insights into the therapeutic potential of curcumin, which involves its properties to act as an epigenetic modulator and target key molecules in colon cancer cells. Full article

Neuroinflammation, a complex nervous system response to brain injury and other pathological stimuli, exhibits a common denominator role in the pathogenesis of neurological disorders and their progression. Among several regulators of neuroinflammation, epigenetic mechanisms with particular emphasis on histone methylation have a prominent role by altering the expression of specific genes involved in the onset and progression of neuroinflammation. The Enhancer of Zeste 2 (EZH2) histone lysine methyltransferase is a multi-faceted and context-dependent regulator of immune response and neural cell function, significantly involved in the underlying mechanisms of neuroinflammation, such as inflammatory gene expression, astrocyte function, microglial activation, BBB integrity, and interactions with non-coding RNAs. Herein, we explore the intricate implication of EZH2 activity in the onset of neuroinflammation and associated pathological conditions, and discuss its potential as a therapeutic target. Currently available EZH2 inhibitors with neuroprotective effects are also addressed in an effort to reveal novel strategies for managing neuroinflammatory conditions, and potentially improving neurological health. 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

Primary failure of tooth eruption (PFE) is a rare genetic disorder characterized by the failure of teeth to erupt in the absence of obvious physical obstructions, often resulting in a progressive open bite that is resistant to orthodontic treatment. While PFE can be caused by genetic or systemic factors (such as cysts, tumors, and endocrine imbalances), the non-syndromic causes are primarily genetic, with an autosomal dominant inheritance pattern with variable expressivity. Several genes have been closely associated with the non-syndromic PFE form. The PTH1R (parathyroid hormone 1 receptor) is the most commonly PFE-associated gene. Additional genes associated with minor frequency are Transmembrane protein 119 (TMEM119), which reduces the glycolytic efficiency of bone cells, limiting their mineralization capacity and causing bone fragility; Periostin (POSTN), which regulates the extracellular matrix and the bone’s response to mechanical stress; and Lysine (K)-specific methyltransferase 2C (KMT2C), which establishes histone methylation near the Wnt Family Member 5A (WNT5A) gene involved in dental development (odontogenesis). Syndromic forms of PFE are typically associated with complex multisystem disorders, where dental eruption failure is one of the clinical features of the spectrum. These syndromes are often linked to genetic variants that affect ectodermal development, craniofacial patterning, and skeletal growth, leading to abnormal tooth development and eruption patterns. Notable syndromes include GAPO syndrome, ectodermal dysplasia, and cleidocranial dysplasia, each contributing to PFE through distinct molecular mechanisms, such as disruptions in dental structure development, cranial abnormalities, or systemic developmental delays. The main aim of this review is to provide a comprehensive overview of the genetic basis underlying both syndromic and non-syndromic forms of PFE to facilitate precision diagnosis, foster the development of personalized therapeutic strategies, and offer new insights into managing this complex dental anomaly. Full article

Background/Objectives: Colorectal cancer (CRC) is the third most common cancer in the US and the second leading cancer-associated mortality cause. Available CRC therapies achieve modest outcomes and fail to prevent its recurrence. Epidemiological studies indicated that the Mediterranean diet rich in olive oil reduced CRC incidence. This study aimed at the identification and assessment of active anti-CRC olive phenolics. Methods: The MTT, wound-healing and colony formation assays were used to discover and assess the in vitro anti-CRC activity of olive phenolics. A nude mouse xenografting model was used to assess the in vivo CRC progression and recurrence suppressive activity of OC in pure and crude forms. OC was isolated from olive oil using liquid–liquid extractions. Results: Screening of olive phenolics for in vitro antiproliferative activity against a diverse panel of CRC cell lines identified the extra-virgin olive oil (EVOO) S-(-)-oleocanthal (OC) as the most active hit. OC showed IC₅₀ values of 4.2, 9.8, 14.5, and 4.9 μM against HCT-116, COLO-320DM, WiDr, and SW48 CRC cells, respectively. The lysine methyltransferases SMYD2 and EZH2, along with the receptor tyrosine kinase c-MET proved aberrantly dysregulated in invasive and metastatic CRC. SMYD2 and c-MET were validated as OC molecular targets in multiple malignancies. Daily oral 10 mg/kg OC treatments over 15 days suppressed 72.5% of the KRAS mutant HCT-116-Luc cells tumors weight in male nude mice. Continued OC daily oral use after primary tumor surgical excision over an additional 40 days significantly suppressed the HCT-116-Luc locoregional tumor recurrence and totally prevented the distant tumor recurrence. The SMYD2-EZH2 expressions and c-MET activation were notably suppressed by OC treatments in vitro and in collected animal primary tumors. Conclusions: OC and olive phenolics are potential nutraceutical interventions useful for CRC control and the prevention of its relapse. Full article

Epigenetic abnormalities play a critical role in colon carcinogenesis, making them a promising target for therapeutic interventions. In this study, we demonstrated that curcumin reduces colon cancer cell survival and that a decrease in lysine methylation was involved in such an effect. This correlated with the downregulation of methyltransferases EZH2, MLL1, and G9a, in both wild-type p53 (wtp53) HCT116 cells and mutant p53 (mutp53) SW480 cells, as well as SET7/9 specifically in wtp53 HCT116 cells. The effects induced by curcumin were more pronounced in wtp53 cells, where it induced a stronger apoptosis and ferroptosis. Interestingly, curcumin also reduced mutp53 expression, suggesting that it could enhance the efficacy of other therapies, particularly in overcoming drug resistance mechanisms associated with mutp53. For instance, in this study, we show that curcumin sensitized SW480 cells to SET7/9 inhibition by sinefungin, further supporting its potential as a combinatorial therapeutic agent. However, although to a lesser extent, curcumin also impaired cell survival in HCT 116 p53 null cells, suggesting that other molecular pathways or factors, beyond p53, may be involved in curcumin-induced cytotoxicity. Full article

Glioblastoma (GBM), the most prevalent primary malignant brain tumor, remains challenging to treat due to extensive inter- and intra-tumor heterogeneity. This variability demands combination treatments to improve therapeutic outcomes. A significant obstacle in treating GBM is the expression of O⁶-methylguanine-DNA methyltransferase, a DNA repair enzyme that reduces the efficacy of the standard alkylating agent, temozolomide, in about 50% of patients. This underscores the need for novel, more targeted therapies. Our study investigates the metabolic–epigenetic impact of combining SN-38, a novel topoisomerase inhibitor inducing DNA double-strand breaks, with rabusertib, a checkpoint kinase 1 inhibitor. We identified this synergistic combination through high-throughput drug screening across a panel of GBM cell lines using a cancer drug library combined with SN-38. A secondary metabolic screening with the PEDS algorithm demonstrated a synergistic modulation of purine, one-carbon, and redox metabolism. Furthermore, the combined treatment led to the significant depletion of epigenetically relevant metabolites such as 5-methyl-cytosine, acetyl-lysine, and trimethyl-lysine. Reduced intermediates of the glutathione cycle indicated increased cellular stress following combinatorial treatment. Overall, the combination of SN-38 and rabusertib synergistically disrupts metabolites associated with epigenetic adaptations, leading to cytotoxicity independent of O⁶-methylguanine-DNA methyltransferase status, thereby underpinning this combination as a promising candidate for combinatorial therapy in GBM. Full article

Histone methyltransferases (HMTs) and histone demethylases (HDMs) are critical enzymes that regulate chromatin dynamics and gene expression through the addition and removal of methyl groups on histone proteins. HMTs, such as PRC2 and SETD2, are involved in the trimethylation of histone H3 at lysine 27 and lysine 36, influencing gene silencing and activation. Dysregulation of these enzymes often leads to abnormal gene expression and contributes to tumorigenesis. In contrast, HDMs including KDM7A and KDM2A reverse these methylation marks, and their dysfunction can drive disease progression. In cancer, the aberrant activity of specific HMTs and HDMs can lead to the silencing of tumor suppressor genes or the activation of oncogenes, facilitating tumor progression and resistance to therapy. Conversely, in neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), disruptions in histone methylation dynamics are associated with neuronal loss, altered gene expression, and disease progression. We aimed to comprehend the odd activity of HMTs and HDMs and how they contribute to disease pathogenesis, highlighting their potential as therapeutic targets. By advancing our understanding of these epigenetic regulators, this review provides new insights into their roles in cancer and neurodegenerative diseases, offering a foundation for future research. Full article

SET and MYND Domain-Containing 2 (Smyd-2), a specific protein lysine methyltransferase (PKMT), influences both histones and non-histones. Its role in cerebral ischemia/reperfusion (CIR), particularly in ferroptosis—a regulated form of cell death driven by lipid peroxidation—remains poorly understood. This study identifies the expression of Smyd-2 in the brain and investigates its relationship with neuronal programmed cell death (PCD). We specifically investigated how Smyd-2 regulates ferroptosis in CIR through its interaction with the Nuclear Factor Erythroid-2-related Factor-2 (Nrf-2)/Kelch-like ECH-associated protein (Keap-1) pathway. Smyd-2 knockout protects HT-22 cells from Erastin-induced ferroptosis but not TNF-α + Smac-mimetic-induced apoptosis/necroptosis. This neuroprotective effect of Smyd-2 knockout in HT-22 cells after Oxygen–Glucose Deprivation/Reperfusion (OGD/R) was reversed by Erastin. Smyd-2 knockout in HT-22 cells shows neuroprotection primarily via the Nuclear Factor Erythroid-2-related Factor-2 (Nrf-2)/Kelch-like ECH-associated protein (Keap-1) pathway, despite the concurrent upregulation of Smyd-2 and Nrf-2 observed in both the middle cerebral artery occlusion (MCAO) and OGD/R models. Interestingly, vivo experiments demonstrated that Smyd-2 knockout significantly reduced ferroptosis and lipid peroxidation in hippocampal neurons following CIR. Moreover, the Nrf-2 inhibitor ML-385 abolished the neuroprotective effects of Smyd-2 knockout, confirming the pivotal role of Nrf-2 in ferroptosis regulation. Cycloheximide (CHX) fails to reduce Nrf-2 expression in Smyd-2 knockout HT-22 cells. Smyd-2 knockout suppresses Nrf-2 lysine methylation, thereby promoting the Nrf-2/Keap-1 pathway without affecting the PKC-δ/Nrf-2 pathway. Conversely, Smyd-2 overexpression disrupts Nrf-2 nuclear translocation, exacerbating ferroptosis and oxidative stress, highlighting its dual regulatory role. This study underscores Smyd-2’s potential for ischemic stroke treatment by disrupting the Smyd-2/Nrf-2-driven antioxidant capacity, leading to hippocampal neuronal ferroptosis. By clarifying the intricate interplay between ferroptosis and oxidative stress via the Nrf-2/Keap-1 pathway, our findings provide new insights into the molecular mechanisms of CIR and identify Smyd-2 as a promising therapeutic target. Full article