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PubMed2006

The contradictory definitions of heterochromatin: transcription and silencing.

Eukaryotic genomes are packaged in two general varieties of chromatin: gene-rich euchromatin and gene-poor heterochromatin. Each type of chromatin has been defined by the presence of distinct chromosomal proteins and posttranslational histone modifications. This review addresses recent findings that appear to blur the definitions of euchromatin and heterochromatin by pointing to the presence of typically heterochromatic modifications (including H3K9me) in euchromatin and typically euchromatic enzymes (including RNA polymerases) in heterochromatin. We discuss the implications of these new findings for the current definition of heterochromatin.

Animals↗
PubMed2005

Kinase Cak1 functionally interacts with the PAF1 complex and phosphatase Ssu72 via kinases Ctk1 and Bur1.

Protein kinases orthologous with Cak1 of Saccharomyces cerevisiae (ScCak1) appear specific to ascomycetes. ScCak1 phosphorylates Cdc28, the cyclin-dependent kinase (CDK) governing the cell cycle, as well as Kin28, Bur1 and Ctk1, CDKs required for the transcription process performed by RNA polymerase II (RNA Pol II). Using genetic methods, we found that Cak1 genetically interacts with Paf1 and Ctr9, two components belonging to the PAF1 elongation complex needed for histone modifications, and with Ssu72, a protein phosphatase that dephosphorylates serine-5 phosphate in the RNA Pol II C-terminal domain. We present evidence suggesting that the interactions linking Cak1 with the PAF1 complex and with Ssu72 are not direct but mediated via Ctk1 and Bur1. We discuss the possibility that Ssu72 intervenes at the capping checkpoint step of the transcription cycle.

Base Sequence↗
PubMed2005

Molecular-pathological prognostic factors of gastric cancer: a review.

Invasion and metastasis are critical determinants of cancer morbidity. Genes and molecules participating in these steps must be regarded as potential prognostic factors. Growth factors and their receptors, cell-cycle regulators, cell-adhesion molecules and matrix-degrading enzymes are those to be used as prognostic factors, including epidermal growth factor (EGF), EGF receptor, K-sam, HER-2, interleukin (IL)-8, vascular endothelial growth factor (VEGF), cyclin E, p27, E-cadherin, CD44v6, matrix metalloproteinase-1 (MMP-1), and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1). Alterations in epigenetics, such as aberrant DNA methylation and histone modification that are, in part, associated with the tumor progression of gastric cancer, can be candidate prognostic factors. The number of methylated genes may serve as a marker of tumor progression. Genetic polymorphism not only affects cancer susceptibility but also influences malignant phenotype; examples include single-nucleotide polymorphism in the HER-2 and MMP-9 genes. Comprehensive gene expression analyses are useful to search for novel genes related to invasion and metastasis and potential prognostic factors. Serial analysis of gene expression (SAGE) has identified several these genes, such as CDH17, APOE, FUS, COL1A1, COL1A2, GW112, and MIA. Overexpression of MIA is found to be associated with poor prognosis. Microarray analysis has great potential for identifying the characteristics of individual cancers, from the view point of gene expression profiles. A combination of these examinations can not only foretell a patient's prognosis but can also give information directly connected with personalized cancer medicine and prevention.

Gene Expression Profiling↗
PubMed2005

Heterochromatin formation: role of short RNAs and DNA methylation.

The role of small double-stranded RNAs is considered in formation of silent chromatin structure. Small RNAs are implicated in the regulation of individual gene transcription, suppression of transposon expression, and in maintaining functional structure of extended heterochromatic regions. Interrelations between short RNA-dependent gene silencing, histone modifications, and DNA methylation are discussed. Specific features of RNA-induced chromatin repression in various eucaryotes are also described.

Animals↗
PubMed2005

The replication timing of CFTR and adjacent genes.

Correlations between transcriptional activity and replication timing have been observed for the human cystic fibrosis transmembrane conductance regulator (CFTR) gene, as well as for other tissue-specific genes. In addition, the patterns of histone modifications and the nuclear positioning of chromosomal loci appear to be related to their replication timing. It is not understood why and how these different features are functionally linked. To address this problem, we investigated the replication timing of the human CFTR gene and of adjacent genes. Recently, we could show that CFTR and adjacent genes associate independently from each other with different nuclear regions and chromatin fractions, in accordance with their individual transcriptional regulation. Together, the results show that not the transcriptional activity, but rather the nuclear position of CFTR and adjacent genes appears to be a major determinant of their replication timing. Furthermore, the results imply a specific functional order of nuclear changes related to switches in replication timing.

Cell Cycle↗
PubMed2006

Identification of a dehydration and ABA-responsive promoter regulon and isolation of corresponding DNA binding proteins for the group 4 LEA gene CpC2 from C. plantagineum.

The resurrection plant Craterostigma plantagineum (Scrophulariaceae) is used as a model system to investigate the molecular and biochemical basis of desiccation tolerance. Genes which contribute to desiccation tolerance are expressed during dehydration of this plant. One of the dehydration-induced genes is CpC2, a group 4 LEA gene. The CpC2 promoter was analysed and a core promoter region (CPR) was identified which is critical for the responsiveness of the gene to dehydration and the plant hormone ABA. The CPR motif contains two ABA-response elements (ABRE) and a binding site for HDZIP transcription factors. A yeast one-hybrid screen was performed to isolate CPR binding proteins. This resulted in the isolation of a bZIP transcription factor (CpbZIP1) and three highly conserved CpHistone H3 proteins. Two of these CpHistone H3 proteins are constitutively expressed histone H3 variants which are suggested to be involved in gene regulation via histone modification. The CpbZIP1 belongs to the group S of bZIP genes which possess long 5'-UTRs with a putative regulatory function. A second very similar bZIP clone, CpbZIP2, was isolated which contains a conserved small upstream open reading frame (uORF) within the 5'-leader sequence. A possible regulatory role of the uORF is discussed.

Abscisic Acid↗
PubMed2026

Research progress on the regulatory mechanisms of the PSY promoter.

Carotenoids are essential pigments in the plant photosynthetic apparatus, functioning in light harvesting, photoprotection, and signal transduction, and serving as precursors of vital nutrients such as vitamin A. Phytoene synthase (PSY) is the first rate-limiting enzyme in the plant carotenoid biosynthetic pathway, and its transcriptional regulation primarily depends on cis-acting promoter elements, associated transcription factors, and epigenetic status. The PSY promoter region contains core cis-elements as well as multiple light-, hormone-, and stress-responsive elements, which collectively function as key regulatory sites governing spatiotemporal expression. This review systematically summarizes recent advances in PSY promoter regulation by plant hormones (e.g., abscisic acid, ethylene, jasmonic acid), environmental factors (light signaling, temperature, salinity, and drought), and epigenetic mechanisms (DNA methylation, histone modifications, and chromatin remodeling). In addition, the application of transgenic and biotechnological approaches to PSY promoter regulation is further summarized. Including promoter sequence engineering with precise editing of cis-elements and promoter-targeted CRISPR activation/interference (CRISPRa/i) for tunable transcriptional control. Emphasis is placed on how these signals are integrated at the promoter level. Deeper insights into these mechanisms will provide both theoretical foundations and practical strategies for enhancing carotenoid accumulation and stress tolerance in crops through molecular design.

Promoter Regions, Genetic↗
PubMed2003

Electrophile tocopheryl quinones in apoptosis and mutagenesis: thermochemolysis of thiol adducts with proteins and in cells.

Electrophile tocopheryl quinones from the phenolic antioxidants gamma-tocopherol and delta-tocopherol form Michael adducts with the thiol nucleophile glutathione. These tocopheryl quinones are involved in cytotoxicity, apoptosis, and mutagenesis, and their biologic properties are associated with the depletion of intracellular thiols. We now show that both proteins and tissues treated with the electrophile gamma-tocopheryl quinone (gamma-TQ) form thiol adducts. The monoglutathion-S-yl derivative of gamma-TQ was subjected to thermochemolysis with the strong methylating base tetramethylammonium hydroxide. GC/MS showed four signature peaks and a fragmentation pattern characteristic of the thiol adduct. Similarly, pure monoglutathion-S-yl and diglutathion-S-yl derivatives of delta-TQ were subjected to thermochemolysis, and GC/MS showed characteristic fragmentation patterns for thiol adducts. The four signature peaks were identified when pure proteins with accessible thiol groups (hemoglobin and histone), FBS, and tissue culture medium and cell preparations were treated with gamma-TQ. Signature peaks in both complete medium and washed cells showed the presence of both soluble and insoluble thiol adducts. The effective or free arylating electrophile concentration in complete medium should always be evaluated in tissue culture studies. gamma-TQ is a mutagen but not a genotoxin; therefore, the histone adduct may be a previously unrecognized histone modification involved in chromatin dynamics leading to mutagenesis.

Apoptosis↗
PubMed1978

Changes in RNA polymerase activity in isolated mouse uterine nuclei during the decidual cell reaction.

The artificially stimulated decidual cell reaction has been used as a model to study changes occurring in the uterus at the time of implantation. Activities of RNA polymerases I, II and III were measured in uterine nuclei isolated from ovariectomized non-primed mice, hormonally primed mice, and hormonally primed mice following stimulation of the decidual cell reaction. Activities of all three RNA polymerases increased following hormonal priming of ovariectomized mice. In nuclei from stimulated uterine horns, activities of RNA polymerases I and III increased 9 h after stimulation of the decidual cell reaction and remained elevated through 21 h. RNA polymerase II activity did not change following stimulation of the decidual cell reaction. These changes in RNA polymerase activities occur at the time of increased histone modifications and may result from changes in the template capacity.

Animals↗
PubMed1980

The interaction of daunorubicin and doxorubicin with DNA and chromatin.

Isotherms that describe the binding of anthracycline antibiotics (including daunorubicin and doxorubicin (adriamycin)) to calf thymus DNA and chromatin have been obtained by means of fluorescence measurements. As expected for charged ligands, the association constants for the interaction of all drugs examined with DNA were found to be dependent on the ionic strength. However, in the case of the daunorubicin-DNA interaction, a marked decrease in the number of binding sites was also observed when the ionic strength was increased. It is suggested that the effect of salt concentration on the number of potential binding sites of daunorubicin molecules to DNA may be the result of some salt-induced alterations in the DNA conformation. This interpretation is also supported by binding data obtained with calf thymus chromatin; Whereas at low salt concentration the binding parameters for the doxorubicin-chromatin interaction are similar to those expected by neutralization of the phosphate groups by histones, modifications of the DNA structure in chromatin are invoked to account for the reduction and heterogeneity of daunorubicin binding sites. The side chain at C-9 could play an important role in determining the strength and specificity of the anthracycline-DNA interaction.

Animals↗
PubMed1979

Short and long-term effects of neuroleptics in relation to their cellular mechanism of action.

1. Some mechanisms of action of neuroleptics at cellular level are reviewed, mainly the effects on synaptic transmission and the effects on chromatin. 2. As regard to the effects at synaptic level, a brief review is presented on the available evidence in support of the currently prevailing dopamine hypothesis. 3. Studies carried out on the mechanisms and sites of action of neuroleptics on chromatin show that: a. Behavioral changes caused by psychotropic drugs in experimental animals are associated with chromatin alterations and induced macromolecular syntheses. b. Parkinsonian and possibly drug-induced extrapyramidal symptoms are associated with aberrations in protein synthesis. c. Destabilization under "stress" of the heterochromatin in schizophrenics seems to be due to histone modifications and is partly prevented by neuroleptic treatment.

Antipsychotic Agents↗
PubMed2006

Epigenetic silencing of gene expression in Entamoeba histolytica.

Transcriptional silencing of an amebapore (ap-a) gene occurred in Entamoeba histolytica following the transfection of plasmids containing a DNA segment (473 bp) homologous to the 5' upstream region of the gene. This segment contains the promoter region of the ap-a gene, a T-rich stretch, followed by a truncated SINE1 (short interspersed element) that is transcribed from the opposite strand. The downstream silencing of the ap-a gene did not occur with plasmids containing the entire SINE1 sequence or lacking the entire SINE1 sequences including the T-rich stretch. Such plasmids promoted the overexpression of the ap-a gene. The transcription of the SINE element required both the T-rich stretch as well as sequences from the 5' end of SINE. RNA extracts from gene-silenced cultures showed small amounts of short (approximately 140 nt), single-stranded molecules with homology to SINE1 transcripts but no siRNA. Chromatin immunoprecipitation (ChIP) analysis of silenced G3 trophozoites with an antibody against methylated K4 of histone H3 revealed a demethylation of K4 at the domain of the ap-a gene indicating transcriptional inactivation. These results suggest the involvement of the SINE1 element in triggering the gene silencing and the role of histone modification in its epigenetic maintenance. The avirulent phenotype of the silenced trophozoites was demonstrated in various assays and the results suggest they may have a potential use for vaccination.

Animals↗
PubMed2026

Histone H3K27ac spreads from enriched chromatin domains into neighboring regions upon loss of CTCF binding.

Acetylation of histone H3 at lysine 27 (H3K27ac) is enriched at enhancers and highly transcribed genes. Our previous study showed that an H3K27ac-enriched chromatin domain expanded into neighboring regions following the deletion of CTCF-binding motifs flanking the domain. In this study, we explored the spreading of H3K27ac on a genome-wide scale by analyzing its distribution around CTCF-binding sites in human K562 cells and examining changes upon CTCF loss. We found that a subset of CTCF-binding sites demarcates H3K27ac-enriched domains. Upon loss of CTCF binding, H3K27ac levels increased in most regions adjacent to these domains, indicating that H3K27ac can spread into neighboring chromatin. This spreading was accompanied by elevated transcription of nearby genes. Chromatin features, including histone modifications, CTCF-binding intensity, and CTCF-mediated chromatin interactions, were associated with the H3K27ac spreading. Notably, enhancers were more enriched within domains that exhibited H3K27ac spreading compared to those that did not, and the deletion of enhancers from the CTCF motif-deficient β-globin locus attenuated the spreading. These findings indicate that CTCF-binding sites serve as boundaries for H3K27ac-enriched domains and that, in the absence of CTCF binding, H3K27ac can spread into neighboring regions. H3K27ac spreading appears to be influenced by multiple chromatin features and to contribute to the transcriptional increase of nearby genes.

CTCF↗
PubMed2006

The orphan nuclear receptor GCNF recruits DNA methyltransferase for Oct-3/4 silencing.

Somatic DNA methylation patterns are determined in part by the de novo methylation that occurs after early embryonic demethylation. Oct-3/4, a pluripotency gene, is unmethylated in the blastocyst, but undergoes de novo methylation and silencing during gastrulation. Here we show that the transcriptional repressor GCNF recruits DNA methyltransferase to the Oct-3/4 promoter and facilitates its methylation. Although acetylation of histone H3 at lysine 9 (K9) and/or 14 (K14) and methylation of H3 at lysine 4 (K4) decrease during this period, as do Oct-3/4 transcript levels, H3K9 and H3K27 methylation levels remain constant, indicating that DNA methylation does not require repressive histone modifications. We found that GCNF interacts directly with Dnmt3 molecule(s) and verified that this interaction induces the methylation of the Oct-3/4 promoter. Our finding suggests a model in which differentiation-induced GCNF recruits de novo DNA methyltransferase and facilitates the silencing of a pluripotency gene.

Animals↗
PubMed2006

Genomic approaches to drug discovery.

Considerable progress has been made in exploiting the enormous amount of genomic and genetic information for the identification of potential targets for drug discovery and development. New tools that incorporate pathway information have been developed for gene expression data mining to reflect differences in pathways in normal and disease states. In addition, forward and reverse genetics used in a high-throughput mode with full-length cDNA and RNAi libraries enable the direct identification of components of signaling pathways. The discovery of the regulatory function of microRNAs highlights the importance of continuing the investigation of the genome with sophisticated tools. Furthermore, epigenetic information including DNA methylation and histone modifications that mediate important biological processes add to the possibilities to identify novel drug targets and patient populations that will benefit from new therapies.

Animals↗
PubMed2006

Cellular memory and dynamic regulation of polycomb group proteins.

Epigenetic components drive the inheritance of transcriptional programs. This cellular memory is crucial for the stable maintenance of cell fates throughout development. Polycomb group (PcG) proteins are central players in various epigenetic phenomena, such as the maintenance of Hox expression patterns from fruit flies to humans, X chromosome inactivation and imprinting in mammals. This cellular memory system involves changes at the chromatin level, through histone modifications and DNA methylation, as well as at the level of the nuclear architecture. Surprisingly, in addition to their role in the stable maintenance of repressive states, PcG factors are involved in more dynamic processes such as cellular proliferation and plasticity.

Adaptation, Biological↗
PubMed2026

Single-cell mapping of regulatory DNA-protein interactions.

Gene expression is controlled by transcription factors (TFs), whose genome binding is shaped by chromatin accessibility and histone modifications, yet mapping these interactions, particularly those with weak affinity or a transient nature, in single cells remains technically challenging. To address this gap, we developed docking and deamination followed by sequencing (D&D-seq), a single-cell immuno-tethering technology for profiling DNA-protein interactions. D&D-seq couples an antibody-binding nanobody to a cytosine base editor, a combination that enables detection of weak or transient factor binding through targeted cytosine-to-uracil editing at protein-bound genomic sites. This approach is compatible with standard single-cell multi-omic workflows and therefore allows integrated analyses of gene regulation. Using assay for transposase-accessible chromatin using sequencing (ATAC-seq) and single-cell ATAC-seq (scATAC-seq), we assessed chromatin accessibility as a functional readout of TF activity, and by coupling D&D-seq with whole-genome sequencing, we captured CTCF binding in both active and inactive chromatin compartments.

Animals↗
PubMed2026

Ketogenic diet dampens excitatory neurotransmission by shrinking synaptic vesicle pools.

Ketogenic diet (KD) is used for the treatment of drug-resistant childhood epilepsy and has been proposed to improve outcomes in neurodegenerative diseases. However, the mechanisms by which KD alters brain circuitry remain unclear. Here, we investigated the impact of KD on hippocampal function through integrative analysis of gene expression and neurotransmission. We found that KD induces extensive transcriptional reprogramming, including altered expression of numerous synaptic genes. Proteomic and genomic profiling revealed significant changes in histone modifications, particularly at promoters of KD-regulated genes. Electrophysiological recordings showed that KD reduces excitatory synaptic gain and short-term plasticity at CA3-CA1 synapses, dampening the summation of excitatory inputs and enhancing the summation of inhibitory inputs. These functional changes were driven, in part, by a reduction in the readily releasable vesicle pool at excitatory synapses under KD. Together, our findings demonstrate that KD drives transcriptional remodeling of hippocampal circuits, leading to synaptic adaptations that may underlie its anti-epileptic and neuroprotective effects.

Animals↗