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Keywords = chromatin folding

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19 pages, 3149 KiB  
Article
Promoter H3K4me3 and Gene Expression Involved in Systemic Metabolism Are Altered in Fetal Calf Liver of Nutrient-Restricted Dams
by Susumu Muroya, Koichi Ojima, Saki Shimamoto, Takehito Sugasawa and Takafumi Gotoh
Int. J. Mol. Sci. 2025, 26(15), 7540; https://doi.org/10.3390/ijms26157540 (registering DOI) - 4 Aug 2025
Abstract
Maternal undernutrition (MUN) causes severe metabolic disruption in the offspring of mammals. Here we determined the role of histone modification in hepatic gene expression in late-gestation fetuses of nutritionally restricted cows, an established model using low-nutrition (LN) and high-nutrition (HN) conditions. The chromatin [...] Read more.
Maternal undernutrition (MUN) causes severe metabolic disruption in the offspring of mammals. Here we determined the role of histone modification in hepatic gene expression in late-gestation fetuses of nutritionally restricted cows, an established model using low-nutrition (LN) and high-nutrition (HN) conditions. The chromatin immunoprecipitation sequencing results show that genes with an altered trimethylation of histone 3 lysine 4 (H3K4me3) are associated with cortisol synthesis and secretion, the PPAR signaling pathway, and aldosterone synthesis and secretion. Genes with the H3K27me3 alteration were associated with glutamatergic synapse and gastric acid secretion. Compared to HN fetuses, promoter H3K4me3 levels in LN fetuses were higher in GDF15, IRF2BP2, PPP1R3B, and QRFPR but lower in ANGPTL4 and APOA5. Intriguingly, genes with the greatest expression changes (>1.5-fold) exhibited the anticipated up-/downregulation from elevated or reduced H3K4me3 levels; however, a significant relationship was not observed between promoter CpG methylation or H3K27me3 and the gene set with the greatest expression changes. Furthermore, the stress response genes EIF2A, ATF4, DDIT3, and TRIB3 were upregulated in the MUN fetal liver, suggesting activation by upregulated GDF15. Thus, H3K4me3 likely plays a crucial role in MUN-induced physiological adaptation, altering the hepatic gene expression responsible for the integrated stress response and systemic energy metabolism, especially circulating lipoprotein lipase regulation. Full article
(This article belongs to the Special Issue Ruminant Physiology: Digestion, Metabolism, and Endocrine System)
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13 pages, 2072 KiB  
Article
Single-Nucleus Chromatin Accessibility and Epigenetic Study Uncover Cell States and Transcriptional Regulation of Epidermis in Hidradenitis Suppurativa
by Safiya Haque, Suha Mohiuddin, Jasim Khan, Suhail Muzaffar, Sudeepthi Vejendla, Yanfeng Zhang, Masakazu Kamata and Lin Jin
Biomedicines 2025, 13(7), 1599; https://doi.org/10.3390/biomedicines13071599 - 30 Jun 2025
Viewed by 385
Abstract
Background/Objectives: Hidradenitis suppurativa (HS) is a complicated chronic inflammatory skin disorder characterized by recurrent and painful deep-seated nodules, abscesses, fistulae, scarring, and sinus tracts. HS most commonly affects high-density hair follicles and apocrine gland-rich regions of the body, including the axillae, inguinal folds, [...] Read more.
Background/Objectives: Hidradenitis suppurativa (HS) is a complicated chronic inflammatory skin disorder characterized by recurrent and painful deep-seated nodules, abscesses, fistulae, scarring, and sinus tracts. HS most commonly affects high-density hair follicles and apocrine gland-rich regions of the body, including the axillae, inguinal folds, breasts, and perianal areas. Although genetic predisposition and environmental factors are known to contribute to the development and the severity of HS, the molecular mechanisms of HS are largely unknown. Methods: In this study, we employed global epigenetic and genomic data analysis and single-nucleus ATAC-seq (snATAC-seq) to profile the heterogeneity of HS-associated chromatin accessibility and define the underlying disease drivers. We additionally performed high-resolution immunofluorescence staining to confirm a novel candidate regulator. Results: We found that multiple skin development modules and molecular signal pathways were epigenetically dysregulated in HS basal CD49fhigh cells. Importantly, our snATAC-seq revealed a previously unraveled role for a transcription factor, ATF3, in transcriptionally regulating HS-associated genes. We also delineated the specific ATF3 expression pattern across the HS lesional skin. Conclusions: We characterize HS-specific epigenetic plasticity and chromatin state at the single-nucleus level and further underscore a possible mechanism for HS pathogenesis. Full article
(This article belongs to the Special Issue Exploring Human Diseases Through Genomic and Genetic Analyses)
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24 pages, 8214 KiB  
Article
Inhibition of RPA32 and Cytotoxic Effects of the Carnivorous Plant Sarracenia purpurea Root Extract in Non-Small-Cell Lung Cancer Cells
by Kuo-Ting Chang, Yu-Cheng Chen, Yi Lien, Yen-Hua Huang and Cheng-Yang Huang
Plants 2025, 14(10), 1426; https://doi.org/10.3390/plants14101426 - 9 May 2025
Viewed by 898
Abstract
The carnivorous plant Sarracenia purpurea has been traditionally used in various ethnobotanical applications, including treatments for type 2 diabetes and tuberculosis-like symptoms. This study investigates the cytotoxic effects of S. purpurea root extract (Sp-R) on human non-small-cell lung cancer (NSCLC) cell lines, including [...] Read more.
The carnivorous plant Sarracenia purpurea has been traditionally used in various ethnobotanical applications, including treatments for type 2 diabetes and tuberculosis-like symptoms. This study investigates the cytotoxic effects of S. purpurea root extract (Sp-R) on human non-small-cell lung cancer (NSCLC) cell lines, including H1975, H838, and A549, focusing on its impact on cell survival, apoptosis, proliferation, and migration. Additionally, its ability to inhibit the single-stranded DNA-binding activity of human RPA32 (huRPA32), a key protein in DNA replication, was evaluated. Extracts from different plant parts (leaf, stem, and root) were prepared using various solvents (water, methanol, ethanol, and acetone) and screened for apoptosis-inducing potential using the chromatin condensation assay. Among these, the acetone-extracted root fraction (Sp-R-A) exhibited the most potent pro-apoptotic effects. The MTT assay demonstrated a dose-dependent cytotoxic effect on NSCLC cells, with IC50 values of 33.74 μg/mL for H1975, 60.79 μg/mL for H838, and 66.52 μg/mL for A549. Migration and clonogenic assays further revealed that Sp-R-A significantly inhibited cancer cell migration and colony formation in a dose-dependent manner. Moreover, Sp-R-A enhanced apoptosis when combined with the EGFR inhibitor afatinib, suggesting a potential synergistic effect. The electrophoretic mobility shift assay confirmed that Sp-R-A significantly inhibited the DNA-binding activity of huRPA32, with an IC50 of 13.6 μg/mL. AlphaFold structural prediction and molecular docking studies indicated that major bioactive compounds in S. purpurea, including α-amyrin, ursolic acid, and betulinaldehyde, strongly interact with the DNA-binding domain of huRPA32, potentially contributing to its inhibitory effect. Overall, these findings suggest that huRPA32 is a potential molecular target of Sp-R-A and the anticancer potential of S. purpurea root extract against NSCLC is highlighted, supporting further investigation into its therapeutic applications. Full article
(This article belongs to the Special Issue Biological Activities of Plant Extracts, 2nd Edition)
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16 pages, 3296 KiB  
Article
miR-4428 and miR-185-5p as Key Modulators of Insulin Sensitivity and Glucose Homeostasis: Insights into Pathways and Therapeutic Potential in Type 2 Diabetes Mellitus
by Yanisa Rattanapan, Thitinat Duangchan, Thaveesak Sai-ong and Takol Chareonsirisuthigul
Biology 2025, 14(4), 424; https://doi.org/10.3390/biology14040424 - 15 Apr 2025
Cited by 1 | Viewed by 557
Abstract
Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and dysregulation of glucose metabolism. MicroRNAs (miRNAs) such as miR-4428 and miR-185-5p play critical roles in post-transcriptional regulation of genes involved in these processes, but their specific contributions to [...] Read more.
Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and dysregulation of glucose metabolism. MicroRNAs (miRNAs) such as miR-4428 and miR-185-5p play critical roles in post-transcriptional regulation of genes involved in these processes, but their specific contributions to T2DM pathogenesis remain unclear. Plasma samples from T2DM patients and non-diabetic controls were analyzed for miR-4428 and miR-185-5p expression using microarray and bioinformatics tools. Target genes were predicted, and pathway enrichment analysis was performed to explore biological roles. Differential expression analysis revealed a 2.3-fold upregulation of miR-4428 and a 14.4-fold downregulation of miR-185-5p in T2DM patients compared to controls. Predicted targets such as ADAR, KLF9, and SOGA1 were linked to glucose metabolism and insulin signaling pathways. Enrichment analysis highlighted associations with neuronal signaling, chromatin remodeling, and metabolic regulation pathways. miR-4428 and miR-185-5p regulate critical insulin sensitivity and glucose metabolism pathways, making them promising biomarkers and therapeutic targets for managing T2DM. Future studies should validate these findings experimentally to advance miRNA-based interventions for T2DM and its complications. Full article
(This article belongs to the Section Biochemistry and Molecular Biology)
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35 pages, 3356 KiB  
Review
Mechanisms of Hormonal, Genetic, and Temperature Regulation of Germ Cell Proliferation, Differentiation, and Death During Spermatogenesis
by María Maroto, Sara N. Torvisco, Cristina García-Merino, Raúl Fernández-González and Eva Pericuesta
Biomolecules 2025, 15(4), 500; https://doi.org/10.3390/biom15040500 - 29 Mar 2025
Cited by 3 | Viewed by 4541
Abstract
Spermatogenesis is a complex and highly regulated process involving the proliferation, differentiation, and apoptosis of germ cells. This process is controlled by various hormonal, genetic, and environmental factors, including temperature. In hormonal regulation, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (T) are [...] Read more.
Spermatogenesis is a complex and highly regulated process involving the proliferation, differentiation, and apoptosis of germ cells. This process is controlled by various hormonal, genetic, and environmental factors, including temperature. In hormonal regulation, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (T) are essential for correct spermatogenesis development from the early stages and spermatogonia proliferation to germ cell maturation. Other hormones, like inhibin and activin, finely participate tuning the process of spermatogenesis. Genetic regulation involves various transcription factors, such as SOX9, SRY, and DMRT1, which are crucial for the development and maintenance of the testis and germ cells. MicroRNAs (miRNAs) play a significant role by regulating gene expression post-transcriptionally. Epigenetic modifications, including DNA methylation, histone modifications, and chromatin remodelling, are also vital. Temperature regulation is another critical aspect, with the testicular temperature maintained around 2–4 °C below body temperature, essential for efficient spermatogenesis. Heat shock proteins (HSPs) protect germ cells from heat-induced damage by acting as molecular chaperones, ensuring proper protein folding and preventing the aggregation of misfolded proteins during thermal stress. Elevated testicular temperature can impair spermatogenesis, increasing germ cell apoptosis and inducing oxidative stress, DNA damage, and the disruption of the blood–testis barrier, leading to germ cell death and impaired differentiation. The cellular mechanisms of germ cell proliferation, differentiation, and death include the mitotic divisions of spermatogonia to maintain the germ cell pool and produce spermatocytes. Spermatocytes undergo meiosis to produce haploid spermatids, which then differentiate into mature spermatozoa. Apoptosis, or programmed cell death, ensures the removal of defective germ cells and regulates the germ cell population. Hormonal imbalance, genetic defects, and environmental stress can trigger apoptosis during spermatogenesis. Understanding these mechanisms is crucial for addressing male infertility and developing therapeutic interventions. Advances in molecular biology and genetics continue to uncover the intricate details of how spermatogenesis is regulated at multiple levels, providing new insights and potential targets for treatment. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanism of Spermatogenesis)
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18 pages, 3733 KiB  
Article
Exploring the Potential Effectiveness of Croton tiglium Oil and Its Nano-Emulsion on Earias insulana (Lepidoptera: Nolidae)
by Karima S. Khater, Marwa M. Abd-Elrhmman, Zeinab M. E. A. Said, Ali A. El-Sayed, Abdelhadi A. I. Ali, Lamya Ahmed Alkeridis, Laila A. Al-Shuraym, Jingwen Wang, Qichun Zhang and Ahmed A. A. Aioub
Insects 2025, 16(1), 72; https://doi.org/10.3390/insects16010072 - 12 Jan 2025
Viewed by 1641
Abstract
Earias insulana Boisd. (Lepidoptera: Nolidae) is a major pest of cotton and other crops in Egypt, and the widespread use of insecticides has led to resistance. This study evaluates, for the first time, the bioactivity of Croton tiglium (Malpighiales: Euphorbiaceae) oil and its [...] Read more.
Earias insulana Boisd. (Lepidoptera: Nolidae) is a major pest of cotton and other crops in Egypt, and the widespread use of insecticides has led to resistance. This study evaluates, for the first time, the bioactivity of Croton tiglium (Malpighiales: Euphorbiaceae) oil and its nano-emulsion (CTNE) against 25 newly hatched larvae of E. insulana Boisd. We assessed their biological effects across different developmental stages and performed histological and ultrastructural examinations. Gas–liquid chromatography (GLC) identified several bioactive compounds in C. tiglium oil crushed dry seeds, including fatty acids, hydrocarbons, and sterols. CTNE showed excellent quality with a zeta potential of −17.7 mV, an average particle size of 54.28 nm, and spherical droplets of 42.42 nm in diameter. The LC50 values for C. tiglium oil and CTNE were 9.02% and 2.70%, respectively. Both treatments significantly impacted the biological characteristics of E. insulana Boisd., including reduced larval and pupal weight, lower adult emergence, decreased fecundity, and increased mortality. Histologically, there was epithelial cell hypotrophy and detachment, while ultrastructural damage included chromatin condensation, nuclear envelope folding, and mitochondrial damage, indicating apoptotic degeneration. These findings suggest C. tiglium oil and CTNE as potential, safe alternatives to chemical insecticides. Full article
(This article belongs to the Special Issue Natural Metabolites as Biocontrol Agents of Insect Pests)
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16 pages, 2535 KiB  
Article
The Avoidance of Purine Stretches by Cancer Mutations
by Aleksandr V. Vikhorev, Ivan V. Savelev, Oksana O. Polesskaya, Michael M. Rempel, Richard A. Miller, Alexandre A. Vetcher and Max Myakishev-Rempel
Int. J. Mol. Sci. 2024, 25(20), 11050; https://doi.org/10.3390/ijms252011050 - 15 Oct 2024
Cited by 1 | Viewed by 1358
Abstract
Purine stretches, sequences of adenine (A) and guanine (G) in DNA, play critical roles in binding regulatory protein factors and influence gene expression by affecting DNA folding. This study investigates the relationship between purine stretches and cancer development, considering the aromaticity of purines, [...] Read more.
Purine stretches, sequences of adenine (A) and guanine (G) in DNA, play critical roles in binding regulatory protein factors and influence gene expression by affecting DNA folding. This study investigates the relationship between purine stretches and cancer development, considering the aromaticity of purines, quantified by methods like Hückel’s rule and NICS calculations, and the importance of the flanking sequence context. A pronounced avoidance of long purine stretches by typical cancer mutations was observed in public data on the intergenic regions of cancer patients, suggesting a role of intergenic sequences in chromatin reorganization and gene regulation. A statistically significant shortening of purine stretches in cancerous tumors (p value < 0.0001) was found. The insights into the aromatic nature of purines and their stacking energies explain the role of purine stretches in DNA structure, contributing to their role in cancer progression. This research lays the groundwork for understanding the nature of purine stretches, emphasizing their importance in gene regulation and chromatin restructuring, and offers potential avenues for novel cancer therapies and insights into cancer etiology. Full article
(This article belongs to the Special Issue Genetic Mutations in Health and Disease)
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26 pages, 11150 KiB  
Article
Expanding Insights: Harnessing Expansion Microscopy for Super-Resolution Analysis of HIV-1–Cell Interactions
by Annett Petrich, Gyu Min Hwang, Laetitia La Rocca, Mariam Hassan, Maria Anders-Össwein, Vera Sonntag-Buck, Anke-Mareil Heuser, Vibor Laketa, Barbara Müller, Hans-Georg Kräusslich and Severina Klaus
Viruses 2024, 16(10), 1610; https://doi.org/10.3390/v16101610 - 15 Oct 2024
Viewed by 5800
Abstract
Expansion microscopy has recently emerged as an alternative technique for achieving high-resolution imaging of biological structures. Improvements in resolution are achieved by physically expanding samples through embedding in a swellable hydrogel before microscopy. However, expansion microscopy has been rarely used in the field [...] Read more.
Expansion microscopy has recently emerged as an alternative technique for achieving high-resolution imaging of biological structures. Improvements in resolution are achieved by physically expanding samples through embedding in a swellable hydrogel before microscopy. However, expansion microscopy has been rarely used in the field of virology. Here, we evaluate and characterize the ultrastructure expansion microscopy (U-ExM) protocol, which facilitates approximately four-fold sample expansion, enabling the visualization of different post-entry stages of the HIV-1 life cycle, focusing on nuclear events. Our findings demonstrate that U-ExM provides robust sample expansion and preservation across different cell types, including cell-culture-adapted and primary CD4+ T-cells as well as monocyte-derived macrophages, which are known HIV-1 reservoirs. Notably, cellular targets such as nuclear bodies and the chromatin landscape remain well preserved after expansion, allowing for detailed investigation of HIV-1–cell interactions at high resolution. Our data indicate that morphologically distinct HIV-1 capsid assemblies can be differentiated within the nuclei of infected cells and that U-ExM enables detection of targets that are masked in commonly used immunofluorescence protocols. In conclusion, we advocate for U-ExM as a valuable new tool for studying virus–host interactions with enhanced spatial resolution. Full article
(This article belongs to the Special Issue Microscopy Methods for Virus Research)
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18 pages, 1345 KiB  
Article
Global Transcriptomic Analysis of Topical Sodium Alginate Protection against Peptic Damage in an In Vitro Model of Treatment-Resistant Gastroesophageal Reflux Disease
by Pelin Ergun, Tina L. Samuels, Angela J. Mathison, Kate Plehhova, Cathal Coyle, Lizzie Horvath and Nikki Johnston
Int. J. Mol. Sci. 2024, 25(19), 10714; https://doi.org/10.3390/ijms251910714 - 5 Oct 2024
Cited by 5 | Viewed by 2434
Abstract
Breakthrough symptoms are thought to occur in roughly half of all gastroesophageal reflux disease (GERD) patients despite maximal acid suppression (proton pump inhibitor, PPI) therapy. Topical alginates have recently been shown to enhance mucosal defense against acid-pepsin insult during GERD. We aimed to [...] Read more.
Breakthrough symptoms are thought to occur in roughly half of all gastroesophageal reflux disease (GERD) patients despite maximal acid suppression (proton pump inhibitor, PPI) therapy. Topical alginates have recently been shown to enhance mucosal defense against acid-pepsin insult during GERD. We aimed to examine potential alginate protection of transcriptomic changes in a cell culture model of PPI-recalcitrant GERD. Immortalized normal-derived human esophageal epithelial cells underwent pretreatment with commercial alginate-based anti-reflux medications (Gaviscon Advance or Gaviscon Double Action), a matched-viscosity placebo control, or pH 7.4 buffer (sham) alone for 1 min, followed by exposure to pH 6.0 + pepsin or buffer alone for 3 min. RNA sequencing was conducted, and Ingenuity Pathway Analysis was performed with a false discovery rate of ≤0.01 and absolute fold-change of ≥1.3. Pepsin-acid exposure disrupted gene expressions associated with epithelial barrier function, chromatin structure, carcinogenesis, and inflammation. Alginate formulations demonstrated protection by mitigating these changes and promoting extracellular matrix repair, downregulating proto-oncogenes, and enhancing tumor suppressor expression. These data suggest molecular mechanisms by which alginates provide topical protection against injury during weakly acidic reflux and support a potential role for alginates in the prevention of GERD-related carcinogenesis. Full article
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14 pages, 2060 KiB  
Article
Unraveling the Role of JMJD1B in Genome Stability and the Malignancy of Melanomas
by Perla Cruz, Diego Peña-Lopez, Diego Figueroa, Isidora Riobó, Vincenzo Benedetti, Francisco Saavedra, Claudia Espinoza-Arratia, Thelma M. Escobar, Alvaro Lladser and Alejandra Loyola
Int. J. Mol. Sci. 2024, 25(19), 10689; https://doi.org/10.3390/ijms251910689 - 4 Oct 2024
Cited by 1 | Viewed by 1271
Abstract
Genome instability relies on preserving the chromatin structure, with any histone imbalances threating DNA integrity. Histone synthesis occurs in the cytoplasm, followed by a maturation process before their nuclear translocation. This maturation involves protein folding and the establishment of post-translational modifications. Disruptions in [...] Read more.
Genome instability relies on preserving the chromatin structure, with any histone imbalances threating DNA integrity. Histone synthesis occurs in the cytoplasm, followed by a maturation process before their nuclear translocation. This maturation involves protein folding and the establishment of post-translational modifications. Disruptions in this pathway hinder chromatin assembly and contribute to genome instability. JMJD1B, a histone demethylase, not only regulates gene expression but also ensures a proper supply of histones H3 and H4 for the chromatin assembly. Reduced JMJD1B levels lead to the cytoplasmic accumulation of histones, causing defects in the chromatin assembly and resulting in DNA damage. To investigate the role of JMJD1B in regulating genome stability and the malignancy of melanoma tumors, we used a JMJD1B/KDM3B knockout in B16F10 mouse melanoma cells to perform tumorigenic and genome instability assays. Additionally, we analyzed the transcriptomic data of human cutaneous melanoma tumors. Our results show the enhanced tumorigenic properties of JMJD1B knockout melanoma cells both in vitro and in vivo. The γH2AX staining, Micrococcal Nuclease sensitivity, and comet assays demonstrated increased DNA damage and genome instability. The JMJD1B expression in human melanoma tumors correlates with a lower mutational burden and fewer oncogenic driver mutations. Our findings highlight JMJD1B’s role in maintaining genome integrity by ensuring a proper histone supply to the nucleus, expanding its function beyond gene expression regulation. JMJD1B emerges as a crucial player in preserving genome stability and the development of melanoma, with a potential role as a safeguard against oncogenic mutations. Full article
(This article belongs to the Special Issue Molecular Research on Epigenetic Modifications)
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16 pages, 2437 KiB  
Article
Polymer Physics Models Reveal Structural Folding Features of Single-Molecule Gene Chromatin Conformations
by Mattia Conte, Alex Abraham, Andrea Esposito, Liyan Yang, Johan H. Gibcus, Krishna M. Parsi, Francesca Vercellone, Andrea Fontana, Florinda Di Pierno, Job Dekker and Mario Nicodemi
Int. J. Mol. Sci. 2024, 25(18), 10215; https://doi.org/10.3390/ijms251810215 - 23 Sep 2024
Cited by 3 | Viewed by 1736
Abstract
Here, we employ polymer physics models of chromatin to investigate the 3D folding of a 2 Mb wide genomic region encompassing the human LTN1 gene, a crucial DNA locus involved in key cellular functions. Through extensive Molecular Dynamics simulations, we reconstruct in silico [...] Read more.
Here, we employ polymer physics models of chromatin to investigate the 3D folding of a 2 Mb wide genomic region encompassing the human LTN1 gene, a crucial DNA locus involved in key cellular functions. Through extensive Molecular Dynamics simulations, we reconstruct in silico the ensemble of single-molecule LTN1 3D structures, which we benchmark against recent in situ Hi-C 2.0 data. The model-derived single molecules are then used to predict structural folding features at the single-cell level, providing testable predictions for super-resolution microscopy experiments. Full article
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14 pages, 2851 KiB  
Article
TFIIB–Termination Factor Interaction Affects Termination of Transcription on Genome-Wide Scale
by Michael J. O’Brien, Jared M. Schrader and Athar Ansari
Int. J. Mol. Sci. 2024, 25(16), 8643; https://doi.org/10.3390/ijms25168643 - 8 Aug 2024
Viewed by 1479
Abstract
Apart from its well-established role in the initiation of transcription, the general transcription factor TFIIB has been implicated in the termination step as well. The ubiquity of TFIIB involvement in termination as well as mechanistic details of its termination function, however, remain largely [...] Read more.
Apart from its well-established role in the initiation of transcription, the general transcription factor TFIIB has been implicated in the termination step as well. The ubiquity of TFIIB involvement in termination as well as mechanistic details of its termination function, however, remain largely unexplored. Using GRO-seq analyses, we compared the terminator readthrough phenotype in the sua7-1 mutant (TFIIBsua7-1) and the isogenic wild type (TFIIBWT) strains. Approximately 74% of genes analyzed exhibited a 2-3-fold increase in readthrough of the poly(A)-termination signal in the TFIIBsua7-1 mutant compared to TFIIBWT cells. To understand the mechanistic basis of TFIIB’s role in termination, we performed the mass spectrometry of TFIIB—affinity purified from chromatin and soluble cellular fractions—from TFIIBsua7-1 and TFIIBWT cells. TFIIB purified from the chromatin fraction of TFIIBWT cells exhibited significant enrichment of CF1A and Rat1 termination complexes. There was, however, a drastic decrease in TFIIB interaction with CF1A and Rat1 complexes in the TFIIBsua7-1 mutant. ChIP assays revealed about a 90% decline in the recruitment of termination factors in the TFIIBsua7-1 mutant compared to wild type cells. The overall conclusion of these results is that TFIIB affects the termination of transcription on a genome-wide scale, and the TFIIB–termination factor interaction plays a crucial role in the process. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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24 pages, 2775 KiB  
Review
Beyond the Usual Suspects: Examining the Role of Understudied Histone Variants in Breast Cancer
by Hejer Dhahri, Wesley N. Saintilnord, Darrell Chandler and Yvonne N. Fondufe-Mittendorf
Int. J. Mol. Sci. 2024, 25(12), 6788; https://doi.org/10.3390/ijms25126788 - 20 Jun 2024
Cited by 2 | Viewed by 2779
Abstract
The incorporation of histone variants has structural ramifications on nucleosome dynamics and stability. Due to their unique sequences, histone variants can alter histone–histone or histone–DNA interactions, impacting the folding of DNA around the histone octamer and the overall higher-order structure of chromatin fibers. [...] Read more.
The incorporation of histone variants has structural ramifications on nucleosome dynamics and stability. Due to their unique sequences, histone variants can alter histone–histone or histone–DNA interactions, impacting the folding of DNA around the histone octamer and the overall higher-order structure of chromatin fibers. These structural modifications alter chromatin compaction and accessibility of DNA by transcription factors and other regulatory proteins to influence gene regulatory processes such as DNA damage and repair, as well as transcriptional activation or repression. Histone variants can also generate a unique interactome composed of histone chaperones and chromatin remodeling complexes. Any of these perturbations can contribute to cellular plasticity and the progression of human diseases. Here, we focus on a frequently overlooked group of histone variants lying within the four human histone gene clusters and their contribution to breast cancer. Full article
(This article belongs to the Special Issue Novel Insight into Epigenomic Studies of Human Disease)
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19 pages, 2944 KiB  
Communication
Neuroprotective Strategies and Cell-Based Biomarkers for Manganese-Induced Toxicity in Human Neuroblastoma (SH-SY5Y) Cells
by Catherine M. Cahill, Sanjan S. Sarang, Rachit Bakshi, Ning Xia, Debomoy K. Lahiri and Jack T. Rogers
Biomolecules 2024, 14(6), 647; https://doi.org/10.3390/biom14060647 - 31 May 2024
Cited by 5 | Viewed by 2177
Abstract
Manganese (Mn) is an essential heavy metal in the human body, while excess Mn leads to neurotoxicity, as observed in this study, where 100 µM of Mn was administered to the human neuroblastoma (SH-SY5Y) cell model of dopaminergic neurons in neurodegenerative diseases. We [...] Read more.
Manganese (Mn) is an essential heavy metal in the human body, while excess Mn leads to neurotoxicity, as observed in this study, where 100 µM of Mn was administered to the human neuroblastoma (SH-SY5Y) cell model of dopaminergic neurons in neurodegenerative diseases. We quantitated pathway and gene changes in homeostatic cell-based adaptations to Mn exposure. Utilizing the Gene Expression Omnibus, we accessed the GSE70845 dataset as a microarray of SH-SY5Y cells published by Gandhi et al. (2018) and applied statistical significance cutoffs at p < 0.05. We report 74 pathway and 10 gene changes with statistical significance. ReactomeGSA analyses demonstrated upregulation of histones (5 out of 10 induced genes) and histone deacetylases as a neuroprotective response to remodel/mitigate Mn-induced DNA/chromatin damage. Neurodegenerative-associated pathway changes occurred. NF-κB signaled protective responses via Sirtuin-1 to reduce neuroinflammation. Critically, Mn activated three pathways implicating deficits in purine metabolism. Therefore, we validated that urate, a purine and antioxidant, mitigated Mn-losses of viability in SH-SY5Y cells. We discuss Mn as a hypoxia mimetic and trans-activator of HIF-1α, the central trans-activator of vascular hypoxic mitochondrial dysfunction. Mn induced a 3-fold increase in mRNA levels for antioxidant metallothionein-III, which was induced 100-fold by hypoxia mimetics deferoxamine and zinc. Full article
(This article belongs to the Special Issue Toxic and Essential Metals in Human Health and Disease 2022-2023)
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21 pages, 5448 KiB  
Article
A Transcriptome Response of Bread Wheat (Triticum aestivum L.) to a 5B Chromosome Substitution from Wild Emmer
by Alexandr Muterko, Antonina Kiseleva and Elena Salina
Plants 2024, 13(11), 1514; https://doi.org/10.3390/plants13111514 - 30 May 2024
Viewed by 914
Abstract
Over the years, alien chromosome substitution has attracted the attention of geneticists and breeders as a rich source of remarkable genetic diversity for improvement in narrowly adapted wheat cultivars. One of the problems encountered along this way is the coadaptation and realization of [...] Read more.
Over the years, alien chromosome substitution has attracted the attention of geneticists and breeders as a rich source of remarkable genetic diversity for improvement in narrowly adapted wheat cultivars. One of the problems encountered along this way is the coadaptation and realization of the genome of common wheat against the background of the introduced genes. Here, using RNA-Seq, we assessed a transcriptome response of hexaploid wheat Triticum aestivum L. (cultivar Chinese Spring) to a 5B chromosome substitution with its homolog from wild emmer (tetraploid wheat T. dicoccoides Koern) and discuss how complete the physiological compensation for this alien chromatin introgression is. The main signature of the transcriptome in the substituted line was a sharp significant drop of activity before the beginning of the photoperiod with a gradual increase up to overexpression in the middle of the night. The differential expression altered almost all biological processes and pathways tested. Because in most cases, the differential expression or its fold change were modest, and this was only a small proportion of the expressed transcriptome, the physiological compensation of the 5B chromosome substitution in common wheat seemed overall satisfactory, albeit not completely. No over- or under-representation of differential gene expression was found in specific chromosomes, implying that local structural changes in the genome can trigger a global transcriptome response. Full article
(This article belongs to the Section Plant Molecular Biology)
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