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At least 991 records · Page 55Linked to original sources
PubMed2002

Chromatin structure of eukaryotic promoters: a changing perspective.

Over the past few years, many studies have attempted to determine the role of nucleosomes as both positive and negative transcription regulators. The emphasis has mostly centered on chromatin remodeling activities and histone modifications, leaving the question of the influence of the higher-order structure out of the spotlight. Recent technical developments allowing direct measurements of size and mechanical properties of in vivo assembled chromatin may shed light on this poorly understood area. This article presents a brief summary of the current knowledge on transcription-dependent chromatin dynamics and how a rather simple agarose electrophoresis method may change the current view on structural changes linked to transcriptional activation of chromatin.

Animals↗
PubMed2006

ChIP-chip comes of age for genome-wide functional analysis.

In the post-genome era, attention has focused on the functions of genome sequences and how they are regulated. The emerging epigenomic changes and the interactions between cis-acting elements and protein factors may play a central role in gene regulation. To understand the crosstalk between DNA and protein on a genome-wide scale, one emerging technique, called ChIP-chip, takes the strategy of combining chromatin immunoprecipitation with microarray. This new high-throughput strategy helps screen the targets of critical transcription factors and profile the genome-wide distribution of histone modifications, which will enable the feasibility of conducting a large-scale study, such as the Human Epigenome Project.

Animals↗
PubMed2006

Epigenetic inactivation of the dioxin-responsive cytochrome P4501A1 gene in human prostate cancer.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD; dioxin) is a toxic environmental contaminant that works through dioxin response elements (DRE) to activate gene expression. We tested the hypothesis that cancer-related epigenetic changes suppress dioxin activation of the cytochrome P4501A1 (CYP1A1) gene. 5-Aza-2'-deoxycytidine (5-aza-CdR), an inhibitor of DNA methylation, increases TCDD-inducible CYP1A1 mRNA expression in cancerous LNCaP cells but not in noncancerous PWR-1E and RWPE-1 cells (all human prostate cell lines). Bisulfite DNA sequencing shows that the TCDD-responsive CYP1A1 enhancer is highly methylated in LNCaP cells but not in RWPE-1 cells. In vivo footprinting experiments reveal that unmethylated DRE sites do not bind protein in response to TCDD in LNCaP cells, whereas inducible DRE occupancy occurs in RWPE-1 cells. Pretreatment of LNCaP cells with 5-aza-CdR partially restores TCDD-inducible DRE occupancy, showing that DNA methylation indirectly suppresses DRE occupancy. Chromatin immunoprecipitation experiments reveal that LNCaP cells lack trimethyl histone H3 lysine 4, a mark of active genes, on the CYP1A1 regulatory region, whereas this histone modification is prevalent in PWR-1E and RWPE-1 cells. We also analyzed CYP1A1 enhancer methylation in human prostate tissue DNA. We do not detect CYP1A1 enhancer methylation in 30 DNA samples isolated from noncancerous prostate tissue. In contrast, 11 of 30 prostate tumor DNA samples have detectable CYP1A1 enhancer methylation, indicating that it is hypermethylated in prostate tumors. This is the first report that shows that CYP1A1 is aberrantly hypermethylated in human prostate cancer and has an altered, inaccessible chromatin structure that suppresses its dioxin responsiveness.

Azacitidine↗
PubMed2006

Dysregulated expression of stem cell factor Bmi1 in precancerous lesions of the gastrointestinal tract.

PURPOSE: It is important to identify the definitive molecular switches involved in the malignant transformation of premalignant tissues. Cellular senescence is a specific characteristic of precancerous tissues, but not of cancers, which might reflect tumorigenesis-protecting mechanisms in premalignant lesions. Polycomb protein Bmi1, which is a potent negative regulator of the p16INK4 gene, suppresses senescence in primary cells and is overexpressed in various cancers. We hypothesized that Bmi1 expression would also be dysregulated in precancerous lesions in human digestive precancerous tissues. EXPERIMENTAL DESIGN: Bmi1 expression was investigated in cancerous and precancerous tissues of the digestive tract. The expression of p16, beta-catenin, and Gli1 and the in vivo methylation status of the p16 gene were also analyzed in serial sections of colonic precancerous lesions. RESULTS: Bmi1 was clearly overexpressed across a broad spectrum of gastrointestinal cancers, and the expression of Bmi1 increased in a manner that reflected the pathologic malignant features of precancerous colonic tissues (low-grade dysplasia, 12.9 +/- 2.0%; high-grade dysplasia, 82.9 +/- 1.6%; cancer, 87.5 +/- 2.4%). p16 was also strongly expressed in high-grade dysplasia, but not in cancers. p16 promoter methylation was detected only in some Bmi1-positive neoplastic cells. CONCLUSIONS: Bmi1 overexpression was correlated with the malignant grades of human digestive precancerous tissues, which suggests that advanced Bmi1 dysregulation might predict malignant progression. The abnormal Bmi1 expression might link to malignant transformation via the disturbance of orderly histone modification.

Cell Line, Tumor↗
PubMed2006

Genomic imprinting in the placenta.

Genomic imprinting is an epigenetic mechanism that is important for the development and function of the extra-embryonic tissues in the mouse. Remarkably all the autosomal genes which were found to be imprinted in the trophoblast (placenta) only are active on the maternal and repressed on the paternal allele. It was shown for several of these genes that their paternal silencing is not dependent on DNA methylation, at least not in its somatic maintenance. Rather, recent studies in the mouse suggest that placenta-specific imprinting involves repressive histone modifications and non-coding RNAs. This mechanism of autosomal imprinting is similar to imprinted X chromosome inactivation in the placenta. Although the underlying reasons remain to be explored, this suggests that imprinting in the placenta and imprinted X inactivation are evolutionarily related.

Animals↗
PubMed2003

Development and validation of a T7 based linear amplification for genomic DNA.

BACKGROUND: Genomic maps of transcription factor binding sites and histone modification patterns provide unique insight into the nature of gene regulatory networks and chromatin structure. These systematic studies use microarrays to analyze the composition of DNA isolated by chromatin immunoprecipitation. To obtain quantities sufficient for microarray analysis, the isolated DNA must be amplified. Current protocols use PCR-based approaches to amplify in exponential fashion. However, exponential amplification protocols are highly susceptible to bias. Linear amplification strategies minimize amplification bias and have had a profound impact on mRNA expression analysis. These protocols have yet to be applied to the analysis of genomic DNA due to the lack of a suitable tag such as the polyA tail. RESULTS: We have developed a novel linear amplification protocol for genomic DNA. Terminal transferase is used to add polyT tails to the ends of DNA fragments. Tail length uniformity is ensured by including a limiting concentration of the terminating nucleotide ddCTP. Second strand synthesis using a T7-polyA primer adapter yields double stranded templates suitable for in vitro transcription (IVT). Using this approach, we are able to amplify as little as 2.5 ng of genomic DNA, while retaining the size distribution of the starting material. In contrast, we find that PCR amplification is biased towards species of greater size. Furthermore, extensive microarray-based analyses reveal that our linear amplification protocol preserves dynamic range and species representation more effectively than a commonly used PCR-based approach. CONCLUSION: We present a T7-based linear amplification protocol for genomic DNA. Validation studies and comparisons with existing methods suggest that incorporation of this protocol will reduce amplification bias in genome mapping experiments.

Bacteriophage T7↗
PubMed2006

SUV39H1 interacts with HTLV-1 Tax and abrogates Tax transactivation of HTLV-1 LTR.

BACKGROUND: Tax is the oncoprotein of HTLV-1 which deregulates signal transduction pathways, transcription of genes and cell cycle regulation of host cells. Transacting function of Tax is mainly mediated by its protein-protein interactions with host cellular factors. As to Tax-mediated regulation of gene expression of HTLV-1 and cellular genes, Tax was shown to regulate histone acetylation through its physical interaction with histone acetylases and deacetylases. However, functional interaction of Tax with histone methyltransferases (HMTase) has not been studied. Here we examined the ability of Tax to interact with a histone methyltransferase SUV39H1 that methylates histone H3 lysine 9 (H3K9) and represses transcription of genes, and studied the functional effects of the interaction on HTLV-1 gene expression. RESULTS: Tax was shown to interact with SUV39H1 in vitro, and the interaction is largely dependent on the C-terminal half of SUV39H1 containing the SET domain. Tax does not affect the methyltransferase activity of SUV39H1 but tethers SUV39H1 to a Tax containing complex in the nuclei. In reporter gene assays, co-expression of SUV39H1 represses Tax transactivation of HTLV-1 LTR promoter activity, which was dependent on the methyltransferase activity of SUV39H1. Furthermore, SUV39H1 expression is induced along with Tax in JPX9 cells. Chromatin immunoprecipitation (ChIP) analysis shows localization of SUV39H1 on the LTR after Tax induction, but not in the absence of Tax induction, in JPX9 transformants retaining HTLV-1-Luc plasmid. Immunoblotting shows higher levels of SUV39H1 expression in HTLV-1 transformed and latently infected cell lines. CONCLUSION: Our study revealed for the first time the interaction between Tax and SUV39H1 and apparent tethering of SUV39H1 by Tax to the HTLV-1 LTR. It is speculated that Tax-mediated tethering of SUV39H1 to the LTR and induction of the repressive histone modification on the chromatin through H3 K9 methylation may be the basis for the dose-dependent repression of Tax transactivation of LTR by SUV39H1. Tax-induced SUV39H1 expression, Tax-SUV39H1 interaction and tethering to the LTR may provide a support for an idea that the above sequence of events may form a negative feedback loop that self-limits HTLV-1 viral gene expression in infected cells.

Base Sequence↗
PubMed2026

IL17 signaling promotes oocyte developmental competence acquisition during maturation.

BACKGROUND: Defects in the acquisition of oocyte developmental competence during the maturation process causes subfertility or infertility in animals and humans. Understanding the regulatory mechanisms of oocyte maturation is essential for reproductive biology and medicine. Follicular fluid (FF) is an important microenvironment governing oocyte maturation. METHODS: A tandem mass tags (TMT)-based comparative FF proteomic analysis was employed to identify FF proteins that are potentially crucial for oocyte maturation. A very large number of pig and mouse oocytes (approximately 20,000) and embryos (over 13,000, including somatic cell nuclear transfer, parthenogenetic activation, and in vitro fertilization embryos) were used to investigate the effects of identified FF proteins on in vitro oocyte maturation and subsequent in vitro and in vivo embryo development. RNA sequencing, quantitative PCR, enzyme-linked immunosorbent assays, and immunofluorescence were used to study the expression patterns and action mechanisms of identified FF proteins in oocytes. In addition, intra-oocyte levels of glutathione and reactive oxygen species were measured to assess redox homeostasis. RESULTS: Interleukin 17D (IL17D) was identified as an important FF protein and it is significantly upregulated in porcine FF during oocyte maturation. IL17D promotes oocyte maturation by enhancing bidirectional communication between oocytes and cumulus cells, via upregulating CX43 expression and transzonal projections, which helps to maintain oocyte redox homeostasis and nuclear-cytoplasmic synchrony. IL17D treatment of oocytes enhances subsequent in vitro and in vivo full-term embryo development by modulating lipid metabolism and histone modification reprogramming. IL17D exerts its function via activating IL17 signaling through binding to CD93. Two other IL17 family members, IL17A and IL17F, also enhance oocyte maturation quality. IL17D displays a conserved expression pattern and function in pig and mouse oocytes. CONCLUSIONS: This study reveals the critical roles of IL17D in regulating oocyte developmental competence acquisition during maturation by activating IL17 signaling. The findings provide valuable insights into the molecular mechanisms underlining oocyte developmental potential acquisition and may help to develop methods for efficient production of oocytes for assisted reproduction.

Animals↗
PubMed2004

REST and peace for the neuronal-specific transcriptional program.

Despite a genetic homogeneity, cells in multicellular organisms are structurally and functionally heterogeneous. The diversity of cell phenotypes exists due to differential transcriptional programs precisely regulated by specific nuclear factors and induced upon differentiation. The differences in gene expression programs arise during development and become heritable during cell proliferation. Over the last few years, research has focused on three molecular mechanisms that mediate epigenetic phenomena: DNA methylation, histone modification, and formation of specialized nuclear domains or territories. All of these processes are dynamic and tightly linked to the organism's development. Here we review advances in understanding the significance of epigenetic mechanisms in the establishment and maintenance of the specialized transcriptional program. We project the accumulated knowledge onto the delineation of the molecular mechanisms by which central nervous system-specific genes are expressed in the nervous system and repressed in other tissues.

Animals↗
PubMed2006

Epigenetic regulation of stem cell differentiation.

Stem cells undergo extensive self-renewal and have the capacity to differentiate along multiple cell lineages. Progression from stem cells into differentiated progeny requires long-lasting changes in gene expression. Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNA-mediated regulatory events, are essential to controlling the heritable cellular memory of gene expression during development. Recent studies on cell fate specification of embryonic and adult stem cells/progenitors have highlighted a general and critical role for dynamic epigenetic regulation in stem cell self-renewal and differentiation.

Adult↗
PubMed2003

Relationship of DNA double-strand breaks to synapsis in Drosophila.

The relationship between synaptonemal complex formation (synapsis) and double-strand break formation (recombination initiation) differs between organisms. Although double-strand break creation is required for normal synapsis in Saccharomyces cerevisiae and the mouse, it is not necessary for synapsis in Drosophila and Caenorhabditis elegans. To investigate the timing of and requirements for double-strand break formation during Drosophila meiosis, we used an antibody that recognizes a histone modification at double-strand break sites, phosphorylation of HIS2AV (gamma-HIS2AV). Our results support the hypothesis that double-strand break formation occurs after synapsis. Interestingly, we detected a low (10-25% of wildtype) number of gamma-HIS2AV foci in c(3)G mutants, which fail to assemble synaptonemal complex, suggesting that there may be both synaptonemal complex-dependent and synaptonemal complex-independent mechanisms for generating double-strand breaks. Furthermore, mutations in Drosophila Rad54 (okr) and Rad51 (spnB) homologs cause delayed and prolonged gamma-HIS2AV staining, suggesting that double-strand break repair is delayed but not eliminated in these mutants. There may also be an interaction between the recruitment of repair proteins and phosphorylation.

Animals↗
PubMed2025

Comparative and systems analyses of Leishmania spp. non-coding RNAs through developmental stages.

Leishmania spp. is the etiological agent of leishmaniases, neglected diseases that seek to be eradicated in the coming years. The life cycle of these parasites involves different host and stress environments. In recent years, many studies have shown that several protein-coding genes are directly involved with the development and host interactions. However, little is still known about the role of non-coding RNAs (ncRNAs) in life cycle progression. In this study, we aimed to identify the genomic structure and function of ncRNAs from Leishmania spp. and to get insights into the repertoire of ncRNAs (RNAome) of this protozoan genus. We studied 26 strains corresponding to 16 different species of Leishmania. Our RNAome analysis revealed the presence of several ncRNAs that are shared among different species, allowing us to differentiate between subgenera as well as between species that are canonically related to visceral leishmaniasis. We also studied co-expression relationships between coding genes and ncRNAs which in the amastigote developmental stage for Leishmania braziliensis and Leishmania donovani revealed the presence of miRNA-like transcripts co-expressed with several coding genes involved in starvation, survival and histone modification. This work represents the first effort to characterize the Leishmania ssp. RNAome, supporting further approaches to better understand the role of ncRNAs in gene regulation, infective process, and host-parasite interaction.

RNA, Untranslated↗
PubMed2004

Methods of epigenetic analysis.

Epigenetics encompasses heritable changes in DNA or its associated proteins except mutations in gene sequence. Many investigators in the field of epigenetics focus on histone modifications and DNA methylation, two molecular mechanisms that are often linked and interdependent. A variety of methods are applied to the study of epigenetic processes, and the past decade has witnessed an exponential increase in novel approaches to elucidate the molecular mysteries of epigenetic inheritance. This chapter summarizes some of the most contemporary methods used to study epigenetics presented throughout the book.

Chromatin↗
PubMed2004

A mosaic genetic screen reveals distinct roles for trithorax and polycomb group genes in Drosophila eye development.

The wave of differentiation that traverses the Drosophila eye disc requires rapid transitions in gene expression that are controlled by a number of signaling molecules also required in other developmental processes. We have used a mosaic genetic screen to systematically identify autosomal genes required for the normal pattern of photoreceptor differentiation, independent of their requirements for viability. In addition to genes known to be important for eye development and to known and novel components of the Hedgehog, Decapentaplegic, Wingless, Epidermal growth factor receptor, and Notch signaling pathways, we identified several members of the Polycomb and trithorax classes of genes encoding general transcriptional regulators. Mutations in these genes disrupt the transitions between zones along the anterior-posterior axis of the eye disc that express different combinations of transcription factors. Different trithorax group genes have very different mutant phenotypes, indicating that target genes differ in their requirements for chromatin remodeling, histone modification, and coactivation factors.

Animals↗
PubMed2025

PATTY corrects open-chromatin bias for improved bulk and single-cell CUT&Tag profiling.

Precise profiling of epigenomes is essential for better understanding chromatin biology and gene regulation. Cleavage Under Targets & Tagmentation (CUT&Tag) is an efficient epigenomic profiling technique that can be performed on a low number of cells and at the single-cell level. With its growing adoption, CUT&Tag datasets spanning diverse biological systems are rapidly accumulating in the field. CUT&Tag assays use the hyperactive transposase Tn5 for DNA tagmentation. Tn5's preference toward accessible chromatin alters CUT&Tag sequence read distributions in the genome and introduces open-chromatin bias that can confound downstream analysis, an issue more substantial in sparse single-cell data. We show that open-chromatin bias extensively exists in published CUT&Tag datasets, including those generated with recently optimized high-salt protocols. To address this challenge, we present PATTY (Propensity Analyzer for Tn5 Transposase Yielded bias), a comprehensive computational method that corrects open-chromatin bias in CUT&Tag data by leveraging accompanying ATAC-seq. By integrating transcriptomic and epigenomic data using machine learning and integrative modeling, we demonstrate that PATTY enables accurate and robust detection of occupancy sites for both active and repressive histone modifications, including H3K27ac, H3K27me3, and H3K9me3, with experimental validation. We further develop a single-cell CUT&Tag analysis framework built on PATTY and show improved cell clustering when using bias-corrected single-cell CUT&Tag data compared to using uncorrected data. Beyond CUT&Tag, PATTY sets a foundation for further development of bias correction methods for improving data analysis for all Tn5-based high-throughput assays.

Journal Article↗
PubMed2006

Board-invited review: intrauterine growth retardation: implications for the animal sciences.

Intrauterine growth retardation (IUGR), defined as impaired growth and development of the mammalian embryo/fetus or its organs during pregnancy, is a major concern in domestic animal production. Fetal growth restriction reduces neonatal survival, has a permanent stunting effect on postnatal growth and the efficiency of feed/forage utilization in offspring, negatively affects whole body composition and meat quality, and impairs long-term health and athletic performance. Knowledge of the underlying mechanisms has important implications for the prevention of IUGR and is crucial for enhancing the efficiency of livestock production and animal health. Fetal growth within the uterus is a complex biological event influenced by genetic, epigenetic, and environmental factors, as well as maternal maturity. These factors impact on the size and functional capacity of the placenta, uteroplacental blood flows, transfer of nutrients and oxygen from mother to fetus, conceptus nutrient availability, the endocrine milieu, and metabolic pathways. Alterations in fetal nutrition and endocrine status may result in developmental adaptations that permanently change the structure, physiology, metabolism, and postnatal growth of the offspring. Impaired placental syntheses of nitric oxide (a major vasodilator and angiogenic factor) and polyamines (key regulators of DNA and protein synthesis) may provide a unified explanation for the etiology of IUGR in response to maternal undernutrition and overnutrition. There is growing evidence that maternal nutritional status can alter the epigenetic state (stable alterations of gene expression through DNA methylation and histone modifications) of the fetal genome. This may provide a molecular mechanism for the role of maternal nutrition on fetal programming and genomic imprinting. Innovative interdisciplinary research in the areas of nutrition, reproductive physiology, and vascular biology will play an important role in designing the next generation of nutrient-balanced gestation diets and developing new tools for livestock management that will enhance the efficiency of animal production and improve animal well being.

Animal Husbandry↗
PubMed2026

Oxidative stress-driven epigenetic reprogramming of immune cells in COPD: from epitranscriptomic and metabolic crosstalk to treatable traits.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome characterized by persistent oxidative stress and maladaptive immune responses, rather than a single disease entity. Oxidative stress not only damages lung tissue but also reprograms immune cells through both classical epigenetic mechanisms (DNA methylation, histone modifications) and epitranscriptomic regulation (m6A RNA methylation), shaping disease endotypes and treatment resistance. This review presents an integrated framework in which redox signals dynamically reshape the epigenetic and epitranscriptomic landscape, thereby locking immune cells into pathogenic states. Metabolic intermediates (S-adenosylmethionine, α-ketoglutarate, succinate, NAD+) serve as critical nodes that connect immunometabolism to both classical epigenetic enzymes and the m6A machinery, thereby linking redox status to RNA fate. Using NETosis as a paradigm, we illustrate how oxidative-epigenetic-metabolic loops sustain neutrophilic inflammation and resolution failure. Finally, we outline a treatable traits framework that integrates these mechanistic insights into precision combination therapies. This conceptual roadmap aims to shift COPD management from symptom control toward durable, mechanism-driven disease modification.

Humans↗
PubMed2026

Multi-omics approaches in idiopathic pulmonary fibrosis: from molecular mechanisms to therapeutic targets and precision medicine.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options and marked molecular heterogeneity. Despite available antifibrotic therapies, disease progression remains poorly predictable, highlighting the need for improved mechanistic understanding and therapeutic targeting. This review summarizes recent advances in multi-omics research to elucidate the molecular mechanisms underlying IPF and to identify potential biomarkers and pharmacological targets. Multi-omics studies, including genomics, epigenomics, transcriptomics, proteomics, metabolomics, microbiome profiling, and single-cell sequencing, have revealed key pathogenic mechanisms in IPF. Genetic susceptibility factors such as MUC5B promoter variants and telomere-related genes contribute to disease risk. Epigenetic regulation, including DNA methylation, histone modifications, and non-coding RNAs, plays a central role in fibrotic remodeling. Transcriptomic and proteomic analyses have identified dysregulated signaling pathways, including TGF-β, mTOR, cellular senescence, and extracellular matrix remodeling. Metabolomic alterations indicate disrupted lipid and amino acid metabolism. Importantly, integration of multi-omics datasets enables the identification of molecular endotypes, candidate biomarkers, and potential therapeutic targets. However, challenges including data integration, tissue heterogeneity, limited cohort size, and the need for functional validation remain important barriers to clinical translation. Continued development of multi-omics approaches may facilitate more accurate disease classification and support the development of personalized therapeutic strategies for IPF.

biomarkers↗