Breast cancer is a major public health concern worldwide, being the most commonly diagnosed cancer among women and a leading cause of cancer-related deaths. Recent studies have highlighted the significance of non-histone methylation in breast cancer, which modulates the activity, interaction, localization, and stability of target proteins. This regulation affects critical processes such as oncogenesis, tumor growth, proliferation, invasion, migration, and immune responses. This review delves into the enzymes responsible for non-histone methylation, such as protein arginine methyltransferases (PRMTs), lysine methyltransferases (KMTs), and demethylases, and explores their roles in breast cancer. By elucidating the molecular mechanisms and functional consequences of non-histone methylation, this review aims to provide insights into novel therapeutic strategies targeting these pathways. The therapeutic potential of targeting non-histone methylation to overcome drug resistance and enhance treatment efficacy in breast cancer is also discussed, highlighting promising avenues for future research and clinical applications.

UNASSIGNED: Osteosarcoma (OS) poses significant challenges in treatment and lacks reliable prognostic markers. Epigenetic alterations play a crucial role in disease progression. This study aimed to develop an accurate prognostic signature for OS using epigenetic modification genes (EMGs).
UNASSIGNED: The Therapeutically Applicable Research to Generate Effective Treatments (TARGET)-OS cohort was analyzed. Univariate Cox analysis identified survival-associated EMGs. Based on least absolute shrinkage and selection operator (LASSO) regression and multivariate analysis, a 6-gene prognostic signature termed the epigenetic modification-related prognostic signature (EMRPS) was derived in the testing cohort. Kaplan-Meier and receiver operating characteristic (ROC) curve analysis confirmed predictive accuracy through internal and external validation (GEO accession GSE21257). A prognostic nomogram incorporating EMRPS and clinical features was constructed. Transcriptomic analysis including differential gene expression, Gene Ontology (GO), gene set enrichment analysis (GSEA), and immune infiltration analysis was conducted to explore mechanisms linking EMRPS to OS prognosis. Additionally, EMRPS impact on drug sensitivity was predicted.
UNASSIGNED: A 6-gene EMRPS comprising DDX24, DNAJC1, HDAC4, SIRT7, SP140 and UHRF2 was successfully developed. The high-risk group showed significantly shorter survival, consistently observed in both internal and external validation. EMRPS demonstrated high predictive efficacy for 1-, 3-, and 5-year overall survival, with area under curve (AUC) >0.85 in training and ~0.7 in testing. The nomogram integrating age, gender, metastasis status, and EMRPS exhibited high predictive performance based on concordance index analysis. Mechanistic analysis indicated the low-risk group had increased immune infiltration and activity with higher immune checkpoint expression, reflecting an immune-activated tumor microenvironment (TME) suitable for immunotherapy. Drug sensitivity analysis revealed the low-risk group had increased sensitivity to cisplatin, a first-line OS chemotherapy.
UNASSIGNED: Our study successfully established an efficient EMRPS and nomogram, highlighting their potential as novel prognostic markers and indicators for selecting appropriate immunotherapy and chemotherapy candidates in OS treatment.

Monobutyl phthalate (MBP) is the primary active metabolite of dibutyl phthalate (DBP), the key plasticizer component. A substantial body of evidence from studies conducted on both animals and humans indicates that MBP exposure could result in harmful impacts on toxicity pathways. In addition, it can seriously affect human and animal reproductive health. In our present study, we showed that exposure to MBP causes abnormal epigenetic modifications in porcine oocytes and failure of early embryonic development. However, glycine (Gly) can protect oocytes and early embryos from damage caused by MBP. Our study indicated a significant decrease in the percentage of porcine oocytes that reached the metaphase II (MII) phase when exposed to MBP. SET-domain-containing 2(SETD2)-mediated H3K36me3 histone methylation was detected, and the results showed that MBP significantly decreased the protein expression of H3K36me3 and SETD2. Moreover, the expression of the DNA break markers γH2AX and the mRNA expression of Asf1a, and Asf1b increased in the MBP group. The detection of DNA methylation marker proteins showed that MBP significantly increased the fluorescence intensity of 5-methylcytosine (5mC). The results from our RT-qPCR analysis demonstrated a significant decrease in the mRNA expression of the DNA methylation-related genes Dnmt1 and Dnmt3a, as well as the embryonic developmental potential-related genes Oct4 and Nanog, in porcine oocytes following exposure to MBP. Additionally, the mRNA expression of p53 significantly increased. Subsequently, the effects of MBP on early embryonic development were examined via parthenogenesis activation (PA) and in vitro fertilization (IVF). Exposure to MBP significantly impacted the development of embryos in both PA and IVF processes. The TUNEL staining data showed that MBP significantly increased embryonic apoptosis. However, Gly can ameliorate MBP-induced defects in oocyte epigenetic modifications and early embryonic development.

FlbA of Aspergillus niger (indirectly) regulates 36 transcription factor (TF) genes. As a result, it promotes sporulation and represses vegetative growth, protein secretion and lysis. In this study, the functions of part of the FlbA-regulated TF genes were studied by using CRISPRoff. This system was recently introduced as an epigenetic tool for modulating gene expression in A. niger. A plasmid encompassing an optimized CRISPRoff system as well as a library of sgRNA genes that target the promoters of the 36 FlbA-regulated TF genes was introduced in A. niger. Out of 24 transformants that exhibited a sporulation phenotype, 12 and 18 strains also showed a biomass and secretion phenotype, respectively. The transforming sgRNAs, and thus the genes responsible for the phenotypes, were identified from five of the transformants. The results show that the genes dofA, dofB, dofC, dofD, and socA are involved in sporulation and extracellular enzyme activity, while dofA and socA also play roles in biomass formation. Overall, this study shows that the multiplexed CRISPRoff system can be effectively used for functional analysis of genes in a fungus.

Microplastics, recognized as emerging contaminants, are commonly observed to be charged in the environment, potentially exerting toxic effects on various organisms. However, the transgenerational reproductive toxicity and underlying mechanisms of polystyrene (PS), particularly carboxyl-modified PS (PS-COOH) and amino-modified PS (PS-NH2), remain largely unexplored. In this study, the parental generation (P0) of Caenorhabditis elegans was subjected to environmental concentrations (0.1-100 μg/L) of PS, PS-COOH, and PS-NH2, with subsequent generations (F1-F4) cultured under normal conditions. Exposure to PS-NH2 at concentrations of 10-100 μg/L exhibited more pronounced reproductive toxicity compared to PS or PS-COOH, resulting in decreased brood size, egg ejection rate, number of fertilized eggs, and cell corpses per gonad. Similarly, maternal exposure to 100 μg/L of PS-NH2 induced more severe transgenerational reproductive effects in C. elegans. Significant increases in H3 on lysine 4 dimethylation (H3K4me2) and H3 on lysine 9 trimethylation (H3K9me3) levels were observed in the subsequent generation, concurrent with the transgenerational upregulation of set-30 and met-2 following parental exposure to PS, PS-COOH, and PS-NH2. Correlation analyses revealed significant associations between the expression of these genes with the reproductive ability. Molecular docking studies suggested that PS-NH2 exhibited higher affinity for SET-30 and MET-2. Further analysis demonstrated that transgenerational effects on reproduction were absent in set-30(gk315) and met-2(n4256) mutants, highlighting the pivotal role of set-30 and met-2 in mediating the transgenerational effect. This study provides novel insights into the environmental risks associated with negatively and positively charged microplastics.

The incidence of colorectal cancer (CRC) is closely linked to metabolic diseases. Accumulating evidence suggests the regulatory role of AMP-activated protein kinase (AMPK) in cancer metabolic reprogramming. In this study, wild-type and AMPK knockout mice were subjected to azoxymethane-induced and dextran sulfate sodium (AOM/DSS)-promoted colitis-associated CRC induction. A stable AMPK-deficient Caco-2 cell line was also established for the mechanistic studies. The data showed that AMPK deficiency accelerated CRC development, characterized by increased tumor number, tumor size, and hyperplasia in AOM/DSS-treated mice. The aggravated colorectal tumorigenesis resulting from AMPK ablation was associated with reduced α-ketoglutarate production and ten-eleven translocation hydroxylase 2 (TET2) transcription, correlated with the reduced mismatch repair protein mutL homolog 1 (MLH1) protein. Furthermore, in AMPK-deficient Caco-2 cells, the mRNA expression of mismatch repair and tumor suppressor genes, intracellular α-ketoglutarate, and the protein level of TET2 were also downregulated. AMPK deficiency also increased hypermethylation in the CpG islands of Mlh1 in both colonic tissues and Caco-2 cells. In conclusion, AMPK deficiency leads to reduced α-ketoglutarate concentration and elevates the suppressive epigenetic modifications of tumor suppressor genes in gut epithelial cells, thereby increasing the risk of colorectal tumorigenesis. Given the modifiable nature of AMPK activity, it holds promise as a prospective molecular target for the prevention and treatment of CRC.

The widespread use of colloidal copper oxide nanoparticles (CuONPs) poses substantial health risks to humans. CuONPs can penetrate the blood-testis barrier and induce spermatocide, and the understanding of the adverse effects of asthenospermia on spermatogenesis, embryonic development, and transgenerational inheritance is limited. In this study, male mice were orally administered different doses of CuONPs via continuous exposure for one spermatozoon development period (35 days) and then exposed without CuONPs for another 35 days. The CuONPs that accumulated in the testes induced oxidative stress (OS), affected the progress of spermatogenesis and sperm capacitation, and compromised epigenetic modifications, resulting in asthenospermia and embryonic development anomalies in male offspring. In a mechanism, CuONP exposure impaired the self-renewal and differentiation of spermatogonial stem cells (SSCs) via the GDNF/PI3K/AKT signaling pathway under OS. Importantly, CuONP exposure was found to potentially lower H3K9me3 levels in paternal sperm, which would further transgenerational transmission and interfere with sperm mitochondrial energy metabolism and motility, leading to asthenospermia and subfertility in the offspring. Collectively, these data reveal a molecular mechanism by which CuONP exposure disturbs H3K9me3 levels via the OS pathway, which further mediates the asthenospermic effects of reproductive failure by interfering with mitochondrial arrangement and formation in the next generation.

The maintenance of normal pregnancy requires appropriate maturation and transformation of various cells, which constitute the microenvironmental regulatory network at the maternal-fetal interface. Interestingly, changes in the cellular components of the maternal-fetal immune microenvironment and the regulation of epigenetic modifications of the genome have attracted much attention. With the development of epigenetics (DNA and RNA methylation, histone modifications, etc.), new insights have been gained into early embryonic developmental stages (e.g., maternal-to-zygotic transition, MZT). Understanding the various appropriate modes of transcriptional regulation required for the early embryonic developmental process from the perspective of epigenetic modifications will help us to provide new targets and insights into the pathogenesis of embryonic failure during further natural fertilization. This review focuses on the loci of action of epigenetic modifications from the perspectives of female germ cell development and embryo development to provide new insights for personalized diagnosis and treatment of abortion.

Transcription factors (TFs) intricately navigate the vast genomic landscape to locate and bind specific DNA sequences for the regulation of gene expression programs. These interactions occur within a dynamic cellular environment, where both DNA and TF proteins experience continual chemical and structural perturbations, including epigenetic modifications, DNA damage, mechanical stress, and post-translational modifications (PTMs). While many of these factors impact TF-DNA binding interactions, understanding their effects remains challenging and incomplete. This review explores the existing literature on these dynamic changes and their potential impact on TF-DNA interactions.

The mucosal barrier is crucial for intestinal homeostasis, and goblet cells are essential for maintaining the mucosal barrier integrity. The proviral integration site for Moloney murine leukemia virus-1 (PIM1) kinase regulates multiple cellular functions, but its role in intestinal homeostasis during colitis is unknown. Here, we demonstrate that PIM1 is prominently elevated in the colonic epithelia of both ulcerative colitis patients and murine models, in the presence of intestinal microbiota. Epithelial PIM1 leads to decreased goblet cells, thus impairing resistance to colitis and colitis-associated colorectal cancer (CAC) in mice. Mechanistically, PIM1 modulates goblet cell differentiation through the Wnt and Notch signaling pathways. Interestingly, PIM1 interacts with histone deacetylase 2 (HDAC2) and downregulates its level via phosphorylation, thereby altering the epigenetic profiles of Wnt signaling pathway genes. Collectively, these findings investigate the unknown function of the PIM1-HDAC2 axis in goblet cell differentiation and ulcerative colitis/CAC pathogenesis, which points to the potential for PIM1-targeted therapies of ulcerative colitis and CAC.