Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Chromatin loop”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 451 records · Page 25Linked to original sources
PubMed2026

Assessing reproducibility of Hi-C chromatin interactions using stratum-adjusted irreproducible discovery rate.

MOTIVATION: Hi-C is a powerful technology for mapping chromatin interactions genome-wide. However, interaction loops identified from Hi-C contact maps often vary across replicate experiments due to experimental noise, making reproducibility assessment essential. A major challenge lies in the genomic distance dependence of interaction strength, which systematically affects reproducibility but is overlooked by existing methods for reproducibility assessment. RESULTS: We introduce Stratum-Adjusted Irreproducible Discovery Rate (SIDR), a novel statistical model that integrates distance stratification into the widely-used Irreproducible Discovery Rate (IDR) framework. SIDR explicitly models the confounding effect of genomic distance, enabling global control of irreproducibility across interaction ranges. Through simulations and real Hi-C datasets, we demonstrate that SIDR improves discriminative power and recovers more biologically meaningful interactions than existing approaches, making it a valuable tool for robust and reproducible Hi-C analysis. AVAILABILITY: The R package SIDR is freely available on GitHub https://github.com/qunhualilab/SIDR.

Chromatin↗
PubMed2003

Characterization of an Mg2+-dependent endonucleolytic activity of the rat hepatocyte nuclear matrix.

Initial degradation of chromatin into high-molecular mass DNA fragments during apoptosis reflects the periodicity of chromatin organization into nuclear matrix-attached loops. In this article, we put forward the hypothesis that this pattern of DNA cleavage is also a result of the localization of an endonuclease on the nuclear matrix. Namely, we observed an endonucleolytic activity of the isolated rat hepatocyte nuclear matrix. It was Mg2+-dependent, with an optimal activity at pH 7.2 in the absence of either Na+ or K+. It was fully active in the presence of Zn2+ and capable of introducing single-strand breaks into plasmid DNA. It did not display a sequence-specific activity. A 23 kDa DNA nuclease that was principally localized on the rat hepatocyte nuclear matrix was detected. The enzyme shared the biochemical requirements with the nuclear matrix endonucleolytic activity, thus we proposed that p23 could be responsible for the endonucleolytic activity of the nuclear matrix. In view of its properties and preferential localization on the nuclear matrix, the endonuclease described herein could be a possible candidate that brings about initial DNA cleavage during apoptosis.

Animals↗
PubMed1998

Transcriptional control: repression by local chromatin modification.

It is becoming increasingly clear that chromatin modification plays a fundamental part in transcriptional control. Recent studies provide new insights into how transcriptional repressors, in addition to blocking activators, may recruit repression complexes that include chromatin modification factors.

Alcohol Oxidoreductases↗
PubMed2002

Global and gene-specific methylation patterns in cancer: aspects of tumor biology and clinical potential.

Heritable alterations of DNA that do not affect the base pair sequence itself but nevertheless regulate the predetermined activity of genes are referred to as epigenetic. Epigenetic mechanisms comprise diverse phenomena including stable feedback loops, nuclear compartmentalization, differential replication timing, heritable chromatin structures, and, foremost, DNA cytosine methylation (1-3). DNA cytosine methylation has recently gained major attention in the field of basic molecular biology as well as in studies of human diseases including cancer. Changes in DNA methylation patterns in human malignancies have been shown to contribute to carcinogenesis in multiple ways. Both hypo- and hypermethylation events have been described in various neoplasias leading to chromosomal instability and transcriptional gene silencing. DNA methylation research has entered the clinical arena and methylation patterns have become a major focus of clinicians seeking novel prognostic factors and therapeutic targets. The following minireview covers aspects of the basic molecular biology of DNA methylation and summarizes its importance in human cancers.

Apoptosis↗
PubMed1982

Morphology and transcriptional activity of mouse oocyte chromosomes.

Lampbrush chromosomes of growing amphibian oocytes carry thousands of lateral loops each of which consists of a chromatin fiber heavily encrusted with nascent ribonucleoprotein fibrils. These are believed to be responsible for the accumulation and maintenance of RNA transcripts found stored in the egg. In the case of mammalian oocytes, lampbrush chromosomes are most likely to occur during the major growth phase and also possibly during pachytene-early diplotene stages of meiosis. We have examined pachytene and early diplotene mouse oocyte chromosomes through the light microscope using sections of plastic-embedded material and air dried spreads stained with either silver nitrate or methyl green pyronin. Our results indicates that the projections radiating from the chromosomal axis are bundles of chromatin fibers rather than single fibers covered with an ribonucleoprotein matrix. These bundles may represent partially unfolded chromomeres. The axis itself could be partially dispersed revealing threads surrounding a fine linear element. -- Little is known about chromosome structure in growing mammalian oocytes, the stage when transcriptional activity is likely to be most rapid. In our preparations chromosomes at this stage appear as partially condensed fuzzy threads of relatively uniform width. In some cases, the fuzzy thread is seen to contain a dense linear core in the center. Thus, during the growth phase, the chromosomes retain a relatively condensed axis, a characteristic of meiotic chromosomes in general. RNA-containing material is found diffusely spread within the nucleus but not specifically associated with the chromosomes. Electron microscopic analysis of spread chromatin from growing oocytes demonstrates that most transcription units possess only one or two nascent ribonucleoprotein fibrils while a few have more. These and other published data indicate that mouse oocytes do not have true lampbrush chromosomes at any stage of their development.

Animals↗
PubMed1993

Differential post-irradiation caffeine response in normal diploid versus SV40-transformed human fibroblasts: potential role of nuclear organization and protein-composition.

To test the hypothesis that the enhancement of cell killing by post-irradiation treatment with caffeine (CAF) is mediated by alterations in chromatin structure, several nuclear parameters were examined in both caffeine-responsive and non-responsive cell lines. Cell killing, as determined by clonogenic assay, was not enhanced by post-irradiation treatment with 5 mM caffeine in a human diploid fibroblast line (AG1522) but an effect was seen in a SV40 T-antigen transformed derivative (1522-a). CAF caused a complete reversal of the radiation-induced G2 + S phase cell-cycle delays in the transformed cell line but only a partial reversal was noted for the parental cell line. The nuclear endpoints examined, which may be indicative of chromatin conformational changes, included enzymatic accessibility, DNA loop structure, and nuclear protein composition. In assays of the ability of DNA to undergo supercoiling changes, it was found that nucleoids isolated from CAF-treated cells had a significantly reduced propidium-iodide relaxable DNA loop size. The constraints to DNA unwinding produced by CAF were also maintained even in the presence of large numbers of single strand breaks produced by a test dose of radiation (10 Gy). This effect did not correlate well with the ability of CAF to enhance radiation-induced cell killing. The two other nuclear endpoints did detect differences between the normal and transformed cell lines. CAF had no effect on the DNase I digestion kinetics of the normal fibroblasts. However, in the transformed cell line, CAF appeared to render an additional 10-15% of the genome accessible to DNase I digestion. Several radiation and CAF-induced changes in the polypeptide pattern of isolated nucleoids were detected after metabolic labelling with 35S-methionine or 32P-orthophosphoric acid. While the identities of these proteins remain to be established, many had relative molecular weights similar to the other reported radiation-altered proteins and human cell cycle control gene products. The present cell lines should provide a convenient system in which to identify a nuclear protein change specifically associated with the ability of CAF to enhance radiation-induced cell killing.

Caffeine↗
PubMed2025

Interpreting the CTCF-mediated sequence grammar of genome folding with AkitaV2.

Interphase mammalian genomes are folded in 3D with complex locus-specific patterns that impact gene regulation. CTCF (CCCTC-binding factor) is a key architectural protein that binds specific DNA sites, halts cohesin-mediated loop extrusion, and enables long-range chromatin interactions. There are hundreds of thousands of annotated CTCF-binding sites in mammalian genomes; disruptions of some result in distinct phenotypes, while others have no visible effect. Despite their importance, the determinants of which CTCF sites are necessary for genome folding and gene regulation remain unclear. Here, we update and utilize Akita, a convolutional neural network model, to extract the sequence preferences and grammar of CTCF contributing to genome folding. Our analyses of individual CTCF sites reveal four predictions: (i) only a small fraction of genomic sites are impactful; (ii) impact is highly dependent on sequences flanking the core CTCF binding motif; (iii) core and flanking nucleotides contribute largely additively to the overall impact of a site; (iv) sites created as combinations of different core and flanking sequences have impacts proportional to the product of their average impacts, i.e. they are broadly compatible. Our analysis of collections of CTCF sites make two predictions for multi-motif grammar: (i) insulation strength depends on the number of CTCF sites within a cluster, and (ii) pattern formation is governed by the orientation and spacing of these sites, rather than any inherent specialization of the CTCF motifs themselves. In sum, we present a framework for using neural network models to probe the sequences instructing genome folding and provide a number of predictions to guide future experimental inquiries.

CCCTC-Binding Factor↗
PubMed1990

Interaction of DNA with nuclear skeleton in rat hepatocytes.

We have characterized fractions liberated from rat liver cell nuclei digested with DNase I and treated with buffers containing 0.1, 0.5 and 2 M NaCl. Analysis of DNA and proteins present in these fractions as well as in nuclear matrix, confirms the chromatin model according to which transcriptionally active loops interact differently with nuclear skeleton than inactive ones.

Animals↗
PubMed2026

R-loops and D-loops: a delicate balance in genomic stability and instability.

R-loops and D-loops are three-stranded nucleic acid structures that have emerged as central regulators of genome stability, gene expression, and DNA metabolism. R-loops form co-transcriptionally or post-transcriptionally when nascent RNA re-anneals with the template DNA strand, generating an RNA: DNA hybrid that displaces the non-template strand into a single-stranded state. These structures are enriched at CpG island promoters, transcription termination sites, and immunoglobulin class-switch regions, where they coordinate transcription regulation, chromatin remodeling, and DNA damage signaling. D-loops are formed when a single-stranded DNA segment pairs with one strand of a duplex and displaces the other, arising through context-dependent mechanisms that include RAD51- or DMC1-mediated strand invasion in homologous recombination, shelterin-assisted invasion at telomeres, and replication-coupled strand displacement at the mitochondrial DNA origin. They serve as indispensable intermediates in double-strand break repair, telomere maintenance, and mitochondrial DNA replication. Recent cryo-electron microscopy studies have resolved the stepwise RAD51-mediated strand exchange mechanism at near-atomic resolution, substantially advancing structural understanding of D-loop biogenesis. Despite their differences in molecular composition, both structures remodel Watson-Crick base pairing and, when dysregulated, are associated with replication fork stalling, transcription-replication conflicts, and aberrant recombination. This review systematically compares the structural features, formation mechanisms, regulatory networks, and biological functions of R-loops and D-loops, with emphasis on their convergent roles in safeguarding genome integrity. We further discuss rapidly evolving detection technologies and emerging therapeutic strategies targeting these structures in cancer and neurodegeneration, identifying key unresolved questions for future investigation.

Genomic Instability↗
PubMed2006

The Drosophila boundary element-associated factors BEAF-32A and BEAF-32B affect chromatin structure.

Binding sites for the Drosophila boundary element-associated factors BEAF-32A and -32B are required for the insulator activity of the scs' insulator. BEAF binds to hundreds of sites on polytene chromosomes, indicating that BEAF-utilizing insulators are an important class in Drosophila. To gain insight into the role of BEAF in flies, we designed a transgene encoding a dominant-negative form of BEAF under GAL4 UAS control. This BID protein encompasses the BEAF self-interaction domain. Evidence is provided that BID interacts with BEAF and interferes with scs' insulator activity and that BEAF is the major target of BID in vivo. BID expression during embryogenesis is lethal, implying that BEAF is required during early development. Expression of BID in eye imaginal discs leads to a rough-eye phenotype, and this phenotype is rescued by a third copy of the BEAF gene. Expression of BID in salivary glands leads to a global disruption of polytene chromatin structure, and this disruption is largely rescued by an extra copy of BEAF. BID expression also enhances position-effect variegation (PEV) of the w(m4h) allele and a yellow transgene inserted into the pericentric heterochromatin of chromosome 2R, while a third copy of the BEAF gene suppresses PEV of both genes. These results support the hypothesis that BEAF-dependent insulators function by affecting chromatin structure or dynamics.

Animals↗
PubMed1998

Chromatin immunoselection defines a TAL-1 target gene.

Despite the major functions of the basic helix-loop-helix transcription factor TAL-1 in hematopoiesis and T-cell leukemogenesis, no TAL-1 target gene has been identified. Using immunoprecipitation of genomic fragments bound to TAL-1 in the chromatin of murine erythro-leukemia (MEL) cells, we found that 10% of the immunoselected fragments contained a CAGATG or a CAGGTG E-box, followed by a GATA site. We studied one of these fragments containing two E-boxes, CAGATG and CAGGTC, followed by a GATA motif, and showed that TAL-1 binds to the CAGGTG E-box with an affinity modulated by the CAGATG or the GATA site, and that the CAGGTG-GATA motif exhibits positive transcriptional activity in MEL but not in HeLa cells. This immunoselected sequence is located within an intron of a new gene co-expressed with TAL-1 in endothelial and erythroid cells, but not expressed in fibroblasts or adult liver where no TAL-1 mRNA was detected. Finally, in vitro differentiation of embryonic stem cells towards the erythro/megakaryocytic pathways showed that the TAL-1 target gene expression followed TAL-1 and GATA-1 expression. These results establish that TAL-1 is likely to activate its target genes through a complex that binds an E-box-GATA motif and define the first gene regulated by TAL-1.

Amino Acid Sequence↗
PubMed1997

CED-4 induces chromatin condensation in Schizosaccharomyces pombe and is inhibited by direct physical association with CED-9.

BACKGROUND: Three principal genes are involved in developmental programmed cell death (PCD) in the nematode worm Caenorhabditis elegans. The ced-3 and ced-4 genes are both required for each PCD, whereas ced-9 acts to prevent the death-promoting actions of these genes in cells that are destined to survive. Vertebrate homologues of both ced-3 and ced-9 have been identified as the genes encoding the caspase cysteine proteases and the Bcl-2 family, respectively. In contrast, no vertebrate homologue of ced-4 is known. The CED-3/caspases are important effectors of apoptosis that are presumed to act by cleaving specific target substrates. However, the molecular functions of the CED-9/Bcl-2 and CED-4 proteins are unknown. The unicellular yeast Schizosaccharomyces pombe shares many general cellular properties with metazoa, but has no identified cell suicide machinery. We have therefore used S. pombe as a naive model cell system in which to examine the biological effects of cell-death proteins. RESULTS: Induction of wild-type ced-4 expression in S. pombe resulted in rapid focal chromatin condensation and lethality. Mutation of the putative nucleotide-binding P-loop motif of CED-4 (K165Q) eliminated the lethal phenotype. Immunolocalization of CED-4 to the condensed chromatin suggested that the phenotype may result from an intrinsic activity of CED-4. Co-expression of ced-9 prevented CED-4-induced chromatin condensation and lethality, and caused the relocalization of CED-4 to endoplasmic reticulum and outer mitochondrial membranes. A direct interaction between CED-4 and CED-9 was confirmed by yeast two-hybrid analysis. CONCLUSIONS: Using S. pombe as a model system in which to assay CED-4 function, we have identified a potential direct role for CED-4 in chromatin condensation. Chromatin condensation is a ubiquitous feature of metazoan apoptosis that has yet to be linked to an effector. The CED-9-mediated rescue of CED-4-induced lethality in this system and the interaction of the two proteins in the yeast two-hybrid analysis suggest that CED-9 inhibits CED-4 action by direct physical association.

Animals↗
PubMed2003

Engineered chromosome regions with altered sequence composition demonstrate hierarchical large-scale folding within metaphase chromosomes.

Mitotic chromosome structure and DNA sequence requirements for normal chromosomal condensation remain unknown. We engineered labeled chromosome regions with altered scaffold-associated region (SAR) sequence composition as a formal test of the radial loop and other chromosome models. Chinese hamster ovary cells were isolated containing high density insertions of a transgene containing lac operator repeats and a dihydrofolate reductase gene, with or without flanking SAR sequences. Lac repressor staining provided high resolution labeling with good preservation of chromosome ultrastructure. No evidence emerged for differential targeting of SAR sequences to a chromosome axis within native chromosomes. SAR sequences distributed uniformly throughout the native chromosome cross section and chromosome regions containing a high density of SAR transgene insertions showed normal diameter and folding. Ultrastructural analysis of two different transgene insertion sites, both spanning less than the full chromatin width, clearly contradicted predictions of simple radial loop models while providing strong support for hierarchical models of chromosome architecture. Specifically, an approximately 250-nm-diam folding subunit was visualized directly within fully condensed metaphase chromosomes. Our results contradict predictions of simple radial loop models and provide the first unambiguous demonstration of a hierarchical folding subunit above the level of the 30-nm fiber within normally condensed metaphase chromosomes.

Animals↗
PubMed1998

Attachment to the nuclear matrix mediates specific alterations in chromatin structure.

The DNA in eukaryotic chromosomes is organized into a series of loops that are permanently attached at their bases to the nuclear scaffold or matrix at sequences known as scaffold-attachment or matrix-attachment regions. At present, it is not clear what effect affixation to the nuclear matrix has on chromatin architecture in important regulatory regions such as origins of replication or the promoter regions of genes. In the present study, we have investigated cell-cycle-dependent changes in the chromatin structure of a well characterized replication initiation zone in the amplified dihydrofolate reductase domain of the methotrexate-resistant Chinese hamster ovary cell line CHOC 400. Replication can initiate at any of multiple potential sites scattered throughout the 55-kilobase intergenic region in this domain, with two subregions (termed ori-beta and ori-gamma) being somewhat preferred. We show here that the chromatin in the ori-beta and ori-gamma regions undergoes dramatic alterations in micrococcal nuclease hypersensitivity as cells cross the G1/S boundary, but only in those copies of the amplicon that are affixed to the nuclear matrix. In contrast, the fine structure of chromatin in the promoter of the dihydrofolate reductase gene does not change detectably as a function of matrix attachment or cell-cycle position. We suggest that attachment of DNA to the nuclear matrix plays an important role in modulating chromatin architecture, and this could facilitate the activity of origins of replication.

Animals↗
PubMed2006

Marking time.

Explore the source record for details and available documents.

ARNTL Transcription Factors↗
PubMed2006

Formation and positioning of nucleosomes: effect of sequence-dependent long-range correlated structural disorder.

The understanding of the long-range correlations (LRC) observed in DNA sequences is still an open and very challenging problem. In this paper, we start reviewing recent results obtained when exploring the scaling properties of eucaryotic, eubacterial and archaeal genomic sequences using the space-scale decomposition provided by the wavelet transform (WT). These results suggest that the existence of LRC up to distances approximately 20-30 kbp is the signature of the nucleosomal structure and dynamics of the chromatin fiber. Actually the LRC are mainly observed in the DNA bending profiles obtained when using some structural coding of the DNA sequences that accounts for the fluctuations of the local double-helix curvature within the nucleosome complex. Because of the approximate planarity of nucleosomal DNA loops, we then study the influence of the LRC structural disorder on the thermodynamical properties of 2D elastic chains submitted locally to mechanical/topological constraint as loops. The equilibrium properties of the one-loop system are derived numerically and analytically in the quite realistic weak-disorder limit. The LRC are shown to favor the spontaneous formation of small loops, the larger the LRC, the smaller the size of the loop. We further investigate the dynamical behavior of such a loop using the mean first passage time (MFPT) formalism. We show that the typical short-time loop dynamics is superdiffusive in the presence of LRC. For displacements larger than the loop size, we use large-deviation theory to derive a LRC-dependent anomalous-diffusion rule that accounts for the lack of disorder self-averaging. Potential biological implications on DNA loops involved in nucleosome positioning and dynamics in eucaryotic chromatin are discussed.

Base Sequence↗
PubMed2026

Genome assembly of Astatotilapia latifasciata uncovers B chromosome-linked chromatin reorganization.

B chromosomes (Bs) are supernumerary genomic elements found in many eukaryotes, yet their full sequence composition, functional potential, and regulatory impact on the host genome remain unclear. Here, we present a chromosome-level genome assembly of the cichlid fish Astatotilapia latifasciata, integrating PacBio long reads, Illumina short reads, and Hi-C chromatin contact maps to resolve both A and B chromosomes. The 0.93 Gb assembly (N50 = 36.2 Mb) includes a 34 Mb B chromosome containing 789 predicted protein-coding genes and a markedly higher density of transposable elements (TEs), especially long terminal repeats (LTR) retrotransposons. Transcriptome profiling revealed that B-linked genes are predominantly transcriptionally repressed relative to their A chromosome paralogs. Hi-C-based chromatin modeling uncovered distinct 3D structural configurations associated with the B chromosome, including fewer topologically associating domains (TADs), reduced loop formation, and altered compartmentalization. These changes are linked to long-range chromatin interactions and genomic rearrangements, suggesting that the B chromosome reshapes the nuclear architecture of the host genome. Our study proposes a potential regulatory role of Bs in genome and provides a genomic resource for investigating chromosome evolution in cichlids.

Animals↗
PubMed2025

The common murine retroviral integration site activating Hhex marks a distal regulatory enhancer co-opted in human early T-cell precursor leukemia.

The Hhex gene encodes a transcription factor that is important for both embryonic and post-natal development, especially of hematopoietic tissues. Hhex is one of the most common sites of retroviral integration in mouse models. We found the most common integrations in AKXD (recombinant inbred strains) T-ALLs occur 57-61kb 3' of Hhex and activate Hhex gene expression. The genomic region of murine leukemia virus (MLV) integrations has features of a developmental stage-specific cis regulatory element (CRE), as evidenced by ATAC-seq in murine progenitor cells and high H3K27 acetylation at the syntenic CRE in human hematopoietic cell lines. With ChIP-exonuclease, we describe occupancy of LIM domain binding protein 1 (LDB1), the constitutive partner of the LIM Only-2 (LMO2), GATA1, and TAL1 transcription factors at GATA sites and at a composite GATA-E box within the CRE. With virtual 4C analysis, we observed looping between this +65kb CRE and the proximal intron one enhancer of HHEX in primary human ETP-ALLs and in normal progenitor cells. Our results show that retroviral integrations at intergenic sites can mark and take advantage of CREs. Specifically, in the case of HHEX activation, this newly described +65kb CRE is co-opted in the pathogenesis of ETP-ALL by the LMO2/LDB1 complex.

Humans↗