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Ectopic activation of rearranged during transfection (RET) has been reported to facilitate lineage differentiation and cell proliferation in different cytogenetic subtypes of acute myeloid leukemia (AML). Herein, we demonstrate that RET is significantly (p < 0.01) upregulated in AML subtypes containing rearrangements of the lysine methyltransferase 2A gene (KMT2A), commonly referred to as KMT2A‐rearranged (KMT2A‐r) AML. Integrating multi‐epigenomics data, we show that the KMT2A‐MLLT3 fusion induces the development of CCCTC‐binding (CTCF)‐guided de novo extrusion enhancer loop to upregulate RET expression in KMT2A‐r AML. Based on the finding that RET expression is tightly correlated with the selective chromatin remodeler and mediator (MED) proteins, we used a small‐molecule inhibitor having dual inhibition against RET and MED12‐associated cyclin‐dependent kinase 8 (CDK8) in KMT2A‐r AML cells. Dual inhibition of RET and CDK8 restricted cell proliferation by producing multimodal oxidative stress responses in treated cells. Our data suggest that epigenetically enhanced RET protects KMT2A‐r AML cells from oxidative stresses, which could be exploited as a potential therapeutic strategy. Rearranged during transfection (RET) proto‐oncogene is epigenetically regulated and highly expressed in KMT2A‐rearranged acute myeloid leukemia subtypes. We developed a novel small‐molecule inhibitor that expressed dual inhibition against RET and mediator protein 12 (MED12)‐associated cyclin‐dependent kinase 8 (CDK8). RET inhibition caused oxidative stress and inhibited leukemic cell growth.

High-risk Multiple Myeloma (MM) patients were found to maintain telomere length (TL), below the margin of short critical length, consistent with proactive overexpression of telomerase. Previously, DNA methylation has been shown as a determinant of telomere-related gene (TRG) expression and TL to assess risk in different types of cancer. We mapped genome-wide DNA methylation in a cohort of newly diagnosed MM (NDMM; n = 53) patients of major molecular subgroups, compared to age-matched healthy donors (n = 4). Differential methylation and expression at TRG-loci were analyzed in combination with overlapping chromatin marks and underlying DNA-sequences. We observed a strong correlation (R2 ≥ 0.5) between DNA methylation and expression amongst selective TRGs, such that demethylation at the promoters of DDX1 and TERF1 were associated to their oncogenic upregulation, while demethylation at the bodies of two key tumor suppressors ZNF208 and RAP1A led to downregulation of the genes. We demonstrated that TRG expression may be controlled by DNA methylation alone or in cooperation with chromatin modifications or CCCTC-binding factor at the regulatory regions. Additionally, we showed that hypomethylated DMRs of TRGs in NDMM are stabilized with G-quadruplex forming sequences, suggesting a crucial role of these epigenetically vulnerable loci in MM pathogenesis. We have identified a panel of five TRGs, which are epigenetically deregulated in NDMM patients and may serve as early detection biomarkers or therapeutic targets in the disease.

Background Oncogenic overexpression of integrin-β7 ( ITGB7 ) in cases of high-risk multiple myeloma (MM) was reported to promote enhanced interactions between neoplastic plasma-B cells and stromal cells to develop cell-adhesion mediated drug resistance. Methods Expression profiles of adhesion related genes were analyzed in a cohort of MM patients containing major IgH translocations or hyperdiploidies (HY), diagnosed at the premalignant monoclonal gammopathy of undetermined significance (MGUS; n  = 103), smoldering multiple myeloma; (SMM; n  = 190) or MM (MM; n  = 53) stage. Differential expression was integrated with loci-specific alterations in DNA-methylation and chromatin marks in MM patients. A CRISPR-based targeted induction of DNA-methylation at the ITGB7 super-enhancer (SE) in MM.1S cells was employed to intersect the impact of cis-regulatory elements on ITGB7 expression. Results ITGB7 was significantly ( p  < 0.05) upregulated in patients with t(14;16) and t(14;20) subgroups in all MGUS, SMM and MM stages, but sporadically upregulated in t(4;14) subgroup at the MM stage. We demonstrate a predetermined enhancer state on ITGB7 in primary-B cells that is maintained under bivalent chromatin, which undergoes a process of chromatin-state alterations and develops into an active enhancer in cases of the t(4;14) subgroup or SE in cases of the t(14;16) subgroup. We also demonstrate that while targeted induction of DNA-methylation at the ITGB7 -SE further upregulated the gene, inhibition of ITGB7 -SE-associated transcription factor bromodomain-4 downregulated expression of the gene. Conclusions Our findings suggest an epigenetic regulation of oncogenic overexpression of ITGB7 in MM cells, which could be critical in MM progression and an attractive therapeutic target.

Overexpression of S100B is routinely used for disease-staging and for determining prognostic outcomes in patients with malignant melanoma. Intracellular interactions between S100B and wild-type (WT)-p53 have been demonstrated to limit the availability of free WT-p53 in tumor cells, inhibiting the apoptotic signaling cascade. Herein, we demonstrate that, while oncogenic overexpression of S100B is poorly correlated (R < 0.3; p > 0.05) to alterations in S100B copy number or DNA methylation in primary patient samples, the transcriptional start site and upstream promoter of the gene are epigenetically primed in melanoma cells with predicted enrichment of activating transcription factors. Considering the regulatory role of activating transcription factors in S100B upregulation in melanoma, we stably suppressed S100b (murine ortholog) by using a catalytically inactive Cas9 (dCas9) fused to a transcriptional repressor, Krüppel-associated box (KRAB). Selective combination of S100b-specific single-guide RNAs and the dCas9-KRAB fusion significantly suppressed expression of S100b in murine B16 melanoma cells without noticeable off-target effects. S100b suppression resulted in recovery of intracellular WT-p53 and p21 levels and concomitant induction of apoptotic signaling. Expression levels of apoptogenic factors (i.e., apoptosis-inducing factor, caspase-3, and poly-ADP ribose polymerase) were altered in response to S100b suppression. S100b-suppressed cells also showed reduced cell viability and increased susceptibility to the chemotherapeutic agents, cisplatin and tunicamycin. Targeted suppression of S100b therefore offers a therapeutic vulnerability to overcome drug resistance in melanoma.

Stable nanocolloids of monoclinic sulfur (β-SNPs) were prepared through ‘water-in-oil microemulsion technique’ at room temperature after suitable modifications of the surface. The morphology (rod shaped; ~50 nm in diameter) and allotropic nature (monoclinic) of the SNPs were investigated with Transmission Electron Microscopy and X-ray Diffraction technique. The surface modification, colloidal stability, and surface topology of β-SNPs were evaluated with Fourier Transform Infrared Spectroscopy, zeta potential analysis, and Atomic Force Microscopy. Thermal decomposition pattern of these nanosized particles was determined by Thermo Gravimetric Analysis (TGA). β-SNPs-colloids expressed excellent antimicrobial activities against a series of fungal and bacterial isolates with prominent deformities at their surface. In contrast, insignificant cytotoxicity was achieved against the human derived hepatoma (HepG2) cell line upon treatment with β-SNPs. A simultaneous study was performed to determine the stock concentration of β-SNP-colloids using a novel high phase liquid chromatographic method. Cumulative results of this study hence, elucidate the stabilization of nanosized monoclinic sulfur at room temperature and their potential antimicrobial efficacy over micron-sized sulfur.

'Nanobiotechnology, basic and applied aspects' is expected to be of tremendous value to the group of scientists, involved in both basic and applied biology and engineering.The proposed book is a comprehensive compendium of basics of nanoscience and its application in biophysical and biomedical problems.

Background: DNMT3B is frequently overexpressed in molecular subsets of acute myeloid leukemia (AML) and is associated with poor prognosis. Unlike DNMT3A, DNMT3B is rarely mutated, suggesting dysregulation through epigenetic mechanisms. The regulatory basis and downstream consequences of DNMT3B overexpression in AML remain incompletely defined. Methods: We integrated analyses of BeatAML, TCGA, and BLUEPRINT cohorts with multi-omic profiling (RNA-seq, DNA methylation, ATAC-seq, and proteomics) in DNMT3B-high AML models. Nanaomycin A (NanA) was used as a DNMT3B-directed functional probe to interrogate cis-regulatory remodeling, transcriptional circuitry, and apoptotic dependencies. Results: DNMT3B overexpression was linked to enhancer-associated chromatin activation rather than recurrent genetic mutation, particularly in CEBPA- and NPM1-mutant AML. NanA exposure produced focal epigenomic remodeling, including 6900 differentially methylated CpGs, with 268 CpGs located within regions of altered chromatin accessibility. These changes were accompanied by coordinated transcriptomic and proteomic reprogramming enriched for cell-cycle, checkpoint, and stress-response pathways. Functionally, DNMT3B perturbation induced redistribution of cell-cycle phases with increased S-phase fraction and progressive apoptosis. Transcriptional profiling demonstrated induction of BH3-only sensitizers (NOXA, PUMA), repression of BCL2, and compensatory upregulation of MCL1 and BCL-XL, collectively reshaping apoptotic dependency. Combined DNMT3B perturbation and BCL2 inhibition produced cooperative cytotoxicity in DNMT3B-high AML models. Conclusion: DNMT3B functions as a context-dependent epigenetic regulator linking enhancer-associated chromatin organization with proliferative control and apoptotic resistance in AML. DNMT3B-directed epigenetic perturbation remodels cis-regulatory circuitry and is associated with increased venetoclax responsiveness, supporting DNMT3B-governed networks as a candidate co-targeting axis in high-risk AML.

Background MED12 is a key regulator of transcription and chromatin architecture, essential for normal hematopoiesis. While its dysregulation has been implicated in hematological malignancies, the mechanisms driving its upregulation in acute myeloid leukemia (AML) remain poorly understood. We investigated MED12 expression across AML subgroups by integrating chromatin accessibility profiling, histone modification landscapes, and DNA methylation (DNAm) patterns. Functional assays using DNMT inhibition were performed to dissect the underlying regulatory mechanisms. Results MED12 shows subtype-specific upregulation in AML compared to hematopoietic stem and progenitor cells, independent of somatic mutations. Chromatin accessibility profiling reveals that the MED12 locus is epigenetically primed in AML blasts, with increased DNase hypersensitivity at regulatory elements. Histone modification analysis demonstrates strong H3K4me3 and H3K27ac enrichment around the transcription start site (TSS), consistent with promoter activation, while upstream and intragenic regions exhibit enhancer-associated marks (H3K4me1, H3K27ac). Notably, hypermethylation within TSS-proximal regulatory regions (TPRRs)—including promoter-overlapping and adjacent CpG islands—correlates with ectopic MED12 overexpression, challenging the canonical view of DNAm as strictly repressive. Functional studies show that DNMT inhibition via 5-azacytidine reduces MED12 expression despite promoter demethylation in cells with hypermethylated TPRRs, suggesting a noncanonical role for DNA methylation in maintaining active transcription. Furthermore, MED12 expression positively correlates with DNMT3A and DNMT3B expression, implicating these methyltransferases in sustaining its epigenetic activation. Conclusion This study identifies a novel regulatory axis in which aberrant DNA methylation, rather than genetic mutation, drives MED12 upregulation in AML. Our findings suggest that TPRR hypermethylation may function noncanonically to support transcriptional activation, likely in cooperation with enhancer elements. These results underscore the importance of epigenetic mechanisms in AML and highlight enhancer-linked methylation as a potential contributor to oncogene dysregulation. Future studies should further explore the role of noncanonical methylation-mediated gene activation in AML pathogenesis and therapeutic targeting.

Enzymes involved in epigenetic processes such as methyltransferases or demethylases are becoming highly utilized for their persistent DNA or histone modifying efficacy. Herein, we have developed an optogenetic toolbox fused to the catalytic domain (CD) of DNA-methyltransferase3A (DNMT3A-CD) or Ten-Eleven Dioxygenase-1 (TET1-CD) for loci-specific alteration of the methylation state at the promoter of Ascl1 (Mash1) , a candidate proneuron gene. Optogenetical protein pairs, CRY2 linked to DNMT3A-CD or TET1-CD and CIB1 fused to a Transcription Activator-Like Element (TALE) locating an Ascl1 promoter region, were designed for site specific epigenetic editing. A differentially methylated region at the Ascl1 promoter, isolated from murine dorsal root ganglion (hypermethylated) and striated cells (hypomethylated), was targeted with these optogenetic-epigenetic constructs. Optimized blue-light illumination triggered the co-localization of TALE constructs with DNMT3A-CD or TET1-CD fusion proteins at the targeted site of the Ascl1 promoter. We found that this spatiotemporal association of the fusion proteins selectively alters the methylation state and also regulates gene activity. This proof of concept developed herein holds immense promise for the ability to regulate gene activity via epigenetic modulation with spatiotemporal precision.

Surface-modified sulfur nanoparticles (SNP) of two different sizes were prepared via a modified liquid-phase precipitation method, using sodium polysulfide and ammonium polysulfide as starting material and polyethylene glycol-400 (PEG-400) as the surface stabilizing agent. Surface topology, size distribution, surface modification of SNPs with PEG-400, quantitative analysis for the presence of sulfur in nanoformulations, and thermal stability of SNPs were determined by atomic force microscopy (AFM), dynamic light scattering (DLS) plus high-resolution transmission electron microscopy (HR-TEM), fourier transform infrared (FT-IR) spectroscopy, energy dispersive X-ray (EDX) spectroscopy, and thermogravimetric analysis (TGA), respectively. A simultaneous study with micron-sized sulfur (S^sup 0^) and SNPs was carried out to evaluate their fungicidal efficacy against Aspergillus niger and Fusarium oxysporum in terms of radial growth, sporulation, ultrastructural modifications, and phospholipid content of the fungal strains using a modified poisoned food technique, spore-germination slide bioassay, environmental scanning electron microscopy (ESEM), and spectrometry. SNPs expressed promising inhibitory effect on fungal growth and sporulation and also significantly reduced phospholipid content. [PUBLICATION ABSTRACT]