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PubMed1994

RNA polymerase: structural determinant of the chromatin loop and the chromosome.

Current models for RNA synthesis involve an RNA polymerase that tracks along a static template. However, research on chromatin loops suggests that the template slides past a stationary polymerase; individual polymerases tie the chromatin fibre into loops and clusters of polymerases determine the basic structure of the interphase and metaphase chromosome. RNA polymerase is then both a player and a manager of the chromosome loop.

Artifacts↗
PubMed1995

Chromatin loop size in human leukemia (HL-60) cells.

Human leukemia (HL-60) cells were treated with 0.1% detergent Joy and chromatin, protruded from the cell, was observed with an electron microscope. It was demonstrated that most, but not all of the protruded chromatin fibers had a loop structure. The average length of the protrusions of chromatin from the nucleus was 8.47 microns. A high magnification revealed that most of the protruded chromatin consisted of beaded nucleosomal fibers. Therefore, the chromatin loop size was estimated to be 315 +/- 47 k base pairs in length. This length is much longer than that of the fragmented DNA seen in the apoptosis of HL-60 cell, conflicting with the hypothesis that the DNA fragmentation is related to the size of the chromatin loop.

Chromatin↗
PubMed1984

Organization of the higher-order chromatin loop: specific DNA attachment sites on nuclear scaffold.

Data are presented for sequence-specific chromatin-loop organization in histone-depleted nuclei from Drosophila melanogaster Kc cells. We find one loop for each of the tandemly repeated histone gene clusters. The attachment site is localized in the A + T rich H1-H3 spacer on a 657 bp fragment. In the cluster of the hsp70 heat-shock genes, in both control and heat-shocked cells, we find two attachment sites in close proximity upstream of regulatory elements. The transcribed sequences are not associated with the nuclear scaffold in control or in heat-shocked cells. A family of attachment sites related by hybridization to those of the hsp70 genes was discovered.

Animals↗
PubMed2004

Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome.

Mutations in MECP2 are associated with Rett syndrome, an X-linked neurodevelopmental disorder. To identify genes targeted by Mecp2, we sequenced 100 in vivo Mecp2-binding sites in mouse brain. Several sequences mapped to an imprinted gene cluster on chromosome 6, including Dlx5 and Dlx6, whose transcription was roughly two times greater in brains of Mecp2-null mice compared with those of wild-type mice. The maternally expressed gene DLX5 showed a loss of imprinting in lymphoblastoid cells from individuals with Rett syndrome. Because Dlx5 regulates production of enzymes that synthesize gamma-aminobutyric acid (GABA), loss of imprinting of Dlx5 may alter GABAergic neuron activity in individuals with Rett syndrome. In mouse brain, Dlx5 imprinting was relaxed, yet Mecp2-mediated silent-chromatin structure existed at the Dlx5-Dlx6 locus in brains of wild-type, but not Mecp2-null, mice. Mecp2 targeted histone deacetylase 1 to a sharply defined, approximately 1-kb region at the Dlx5-Dlx6 locus and promoted repressive histone methylation at Lys9 at this site. Chromatin immunoprecipitation-combined loop assays showed that Mecp2 mediated the silent chromatin-derived 11-kb chromatin loop at the Dlx5-Dlx6 locus. This loop was absent in chromatin of brains of Mecp2-null mice, and Dlx5-Dlx6 interacted with far distant sequences, forming distinct active chromatin-associated loops. These results show that formation of a silent-chromatin loop is a new mechanism underlying gene regulation by Mecp2.

Animals↗
PubMed2005

[In silico identification and characterization of meiotic DNA: AluJb possibly participates in the attachment of chromatin loops to synaptonemal complex].

Earlier, using bioinformatic methods, we reported the identification of repeated DNA sequences (RS), presumably responsible for the attachment of chromatin loops to the lateral elements of synaptonemal complex in meiotic chromosomes. In the present study, consensus sequences for this class of RS were identified. It was demonstrated that at least part of these sequences belonged to the AluJb subfamily of Alu sequences. The Alu copies distribution along the major human histocompatibility complex (MHC) and their spatial separation from the sites of meiotic recombination was examined. It was demonstrated that simple sequences, like (GC/CA)n, were flanking meiotic recombination sites. A model of the RS organization in meiotic chromosome, most efficiently linking experimental data on the meiotic recombination in MHC and the in silico data on the RS localization (the coefficient of multiple correlation, r = 0.92) is suggested.

Alu Elements↗
PubMed2001

Re-defining the chromatin loop domain.

It is commonly accepted that the loop domain represents the basic structural unit of eukaryotic chromatin associated with DNA replication, gene expression and higher order packaging. However, molecular-cytological information defining the loop domain is lacking. There are gaps in our knowledge of the loop structure and how it regulates gene expression. The combination of new data/reagents from the Human Genome Project plus the use of novel molecular cytological technology will provide answers. Here we briefly review the status of chromatin loop research and pose questions that need to be addressed. New experimental systems are also presented to target some long-standing issues regarding the structure and function of the chromatin loop domain and its relationship with the nuclear matrix. This new knowledge will have a profound impact for modern genetics and molecular medicine.

Animals↗
PubMed1989

Electron microscopic studies on chromatin loop of rat ascites hepatoma cells.

Isolated nuclei from rat ascites hepatoma cells were treated with 0.09% detergent Joy and chromatin, protruded from the nucleus, was observed with an electron microscope. It was demonstrated that most, but not all of the protruded chromatin fibers had a loop structure. The protrusion of chromatin from the nucleus was 3 microns in average length. A high magnification view showed that the protruded chromatin consisted mainly of beaded nucleosomal fiber. Therefore, the chromatin loop size at the level of nucleosomal fiber was estimated to be at least 6 microns in length.

Animals↗
PubMed2006

Modeling a self-avoiding chromatin loop: relation to the packing problem, action-at-a-distance, and nuclear context.

There is now convincing evidence that genomes are organized into loops, and that looping brings distant genes together so that they can bind to local concentrations of polymerases in "factories" or "hubs." As there remains no systematic analysis of how looping affects the probability that a gene can access binding sites in such factories/hubs, we used an algorithm that we devised and Monte Carlo methods to model a DNA or chromatin loop as a semiflexible (self-avoiding) tube attached to a sphere; we examine how loop thickness, rigidity, and contour length affect where particular segments of the loop lie relative to binding sites on the sphere. Results are compared with those obtained with the traditional model of an (infinitely thin) freely jointed chain. They provide insights into the packing problem (how long genomes are packed into small nuclei), and action-at-a-distance (how firing of one origin or gene can prevent firing of an adjacent one).

Algorithms↗
PubMed2026

Engineering chromatin loops to control cell fate: LoopID reveals catalytic-independent functions of epigenetic regulators.

Enhancer-promoter (E-P) interactions are central to cell-type-specific transcriptional programs, yet the molecular machinery that establishes and maintains these loops has remained poorly defined. A recent study by Jiang et al, published in Nature Genetics, presents a series of transformative discoveries that redefine our understanding of E-P interactions and their role in gene regulation and cell fate determination. The research introduces LoopID, a chromatin-interaction-based proteomic platform that, for the first time, enables systematic identification of protein components, termed the "looposome," localized specifically at chromatin looping anchors. Using LoopID, they profile the "looposome" in mouse embryonic stem cells (ESCs) and uncover an unexpected, catalytic-independent role for the histone demethylase JMJD2 (KDM4) in organizing chromatin architecture through phase-separated condensates. Beyond mechanism, the study demonstrates that targeted assembly of JMJD2 condensates at defined genomic loci can engineer E-P interactions driving cellular reprogramming toward pluripotent and two-cell-like states. Together, these findings represent not only a major technical advance but also a conceptual leap-establish LoopID as a foundational technology for dissecting chromatin structure, introduce a new conceptual framework for epigenetic regulators as structural organizers, and provide a powerful strategy to manipulate cell fate by rewiring three-dimensional (3D) genome architecture.

Animals↗
PubMed2006

Chromatin loops are responsible for higher counts of small DNA fragments induced by high-LET radiation, while chromosomal domains do not affect the fragment sizes.

PURPOSE: To apply a polymer model of DNA damage induced by high-LET (linear energy transfer) radiation and determine the influence of chromosomal domains and loops on fragment length distribution. MATERIALS AND METHODS: The yields of DSB (double-strand breaks) induced by high-LET radiation were calculated using a track structure model along with a polymer model of DNA packed in the cell nucleus. The cell nucleus was constructed to include the chromosomal domains and chromatin loops. The latter were generated by the random walk method. RESULTS AND CONCLUSIONS: We present data for DSB yields per track per cell, DNA fragment sizes, the radial distribution of DSB with respect to the track center, and the distribution of 0, 1, 2, and more DSB from a single particle. Calculations were carried out for a range of particles including He (40 keV/microm), N (225 keV/microm), and Fe ions (150 keV/mum). Situations relevant to PFGE (pulsed-field gel electrophoresis) and microbeam experiments with direct irradiation of the cell nucleus were simulated to demonstrate the applicability of the model. Data show that chromosomal domains do not have a significant influence on fragment-size distribution, while the presence of DNA loops increases the frequencies of smaller fragments by nearly 30% for fragment sizes in the range from 2 kbp (bp = base pair) to 20 kbp.

Chromatin↗
PubMed2007

Chromatin looping mediates boundary element promoter interactions.

One facet of the control of gene expression is long-range promoter regulation by distant enhancers. It is an important component of the regulation of genes that control metazoan development and has been appreciated for some time but the molecular mechanisms underlying this regulation have remained poorly understood. A recent study by Cleard and colleagues1 reports the first in vivo evidence of chromatin looping and boundary element promoter interaction. Specifically, they studied the function of a boundary element within the cis-regulatory region of the Abdominal-B (Abd-B) gene of Drosophila melanogaster.

Animals↗
PubMed1993

Multitude of inverted repeats characterizes a class of anchorage sites of chromatin loops to the nuclear matrix.

In order to understand the nature of DNA sequences that organize chromatin into domains or loops, we have cloned the nuclear matrix DNA (1.7% of the total DNA) from human myelogenous leukemia cells in culture. Nuclear matrix is formed by interactions between specific stretches of DNA of about 0.1 to 5.0 kb with protein transcription factors, nuclear enzymes, and structural proteins. Nuclear matrix is believed to be the exclusive nuclear microenvironment in which initiation of DNA replication, transcription, and repair take place. The matrix attachment regions (MARs) of DNA have transcriptional enhancer activity, harbor the origins of replication of the human genome, and define the borders between neighboring chromatin loops. In this study we report the sequence of the human MAR fragment 19.2 of a size of 542 bp. Hum. MAR 19.2 is composed of TG-, CA-, CT-, and GA-rich blocks and shows 8 perfect and imperfect inverted repeats. Thus, we have identified a novel class of MARs with sequence characteristics divergent from the AT-rich class of MARs. The inverted repeats of the 19.2 sequence might be stabilized into their cruciform configuration by torsional strain and by specific transcription/replication protein factors. This MAR might function in the initiation of replication of the flanking chromatin domain and in the regulation of the transcriptional activity of the gene(s) that reside in this domain.

Base Sequence↗
PubMed1992

The attachments of chromatin loops to the nucleoskeleton.

It is widely assumed by cell biologists that chromatin is looped by attachment to some nuclear skeleton. 'Structural' attachments might be mediated through specific sequences; these would be attached in most cells in an organism, underlying the basic structure of the mitotic chromosome and persisting throughout interphase. 'Functional' attachments might also exist, perhaps if active polymerases are attached to the skeleton and replication and transcription occur as DNA is reeled through them. Cells of different tissues--and even cells of the same tissue--would have different attachments of this type. Problems associated with demonstrating these two kinds of attachment are discussed. We find little good evidence for 'structural' attachments and explore the idea that 'functional' attachments are the only kind that exist: 'functional' attachments involving active transcription units might be stable enough to organize chromatin during both interphase and mitosis, but 'dynamic' enough to allow duplication of attached sequences without disrupting loops.

Animals↗
PubMed2002

Structure, function and DNA composition of Saccharomyces cerevisiae chromatin loops.

Recent localization of cohesin association regions along the yeast chromatin fibre suggests that compositional variability of DNA in yeast is related to the function and organization of the chromosomal loops. The bases of the loops, where the chromatin fibre is attached to the chromosomal axis, are AT-rich, bind cohesin, and are flanked by genes transcribed convergently. The hotspots of meiotic recombination are mainly found in the GC-rich parts of the loops, 'external' with respect to the chromosomal axis, frequently in the vicinity of the promoters of divergently transcribed genes. There are two possible reasons why the regions of the hotspots of recombination were enriched in GC content during evolution. One is a biased repair of recombination intermediates, and the second is a selective advantage due to an increased chromatin accessibility, which may have the carriers of GC-enriched alleles over the carriers of AT-rich alleles.

Base Composition↗
PubMed1990

The size of chromatin loops in HeLa cells.

It is widely believed that the chromatin fibre is organized into loops during interphase, with the loop being implicated as an important unit of nuclear function. However, there remains little direct evidence for looping, with estimates of loop size varying widely. This has led to the suggestion that some loops, or even all of them, arise artefactually during isolation as chromatin aggregates so easily. We have now investigated the effect of isolation procedure on loop size using HeLa cells encapsulated in agarose to allow easy manipulation. Loop size in various derivatives (i.e. nuclei, nucleoids, matrices and scaffolds) critically depended on procedure; some (or all) of their loops are artefacts. The loop size in derivatives isolated using the most 'physiological' conditions was 86 kb; this remained unchanged throughout the cell cycle. This loop size is probably an average of a range of loops of between 5 and 200 kb.

Cell Cycle↗
PubMed1989

Chromatin loop structure of the human X chromosome: relevance to X inactivation and CpG clusters.

Part of the higher-order structure of chromatin is achieved by constraining DNA in loops ranging in size from 30 to 100 kilobase pairs; these loops have been implicated in defining functional domains and replicons and possibly in facilitating transcription. Because the human active and inactive X chromosomes differ in transcriptional activity and replication, we looked for differences in their chromatin loop structures. Since the islands of CpG-rich DNA at the 5' ends of X-linked housekeeping genes are the regions where functional differences in DNA methylation and nuclease sensitivity are found, we looked for scaffold association of these sequences after extraction of histones with lithium diiodosalicylate. Specifically, we examined the 5' CpG islands within the hypoxanthine phosphoribosyltransferase, glucose 6-phosphate dehydrogenase, P3, GdX, phosphoglycerate kinase type 1, and alpha-galactosidase loci in human lymphoblasts obtained from individuals with 1 to 4 X chromosomes. Although we detected no scaffold-associated regions near these genes, we found several such regions at the ornithine transcarbamylase and blood clotting factor IX loci. Our results suggest that the CpG islands are excluded from the nuclear scaffold and that even though transcriptionally active, housekeeping genes are less likely than X-linked tissue-specific genes to be scaffold associated. In all cases, the pattern of scaffold association was the same for loci on active and inactive X chromosomes.

Animals↗
PubMed2004

Interaction between differentially methylated regions partitions the imprinted genes Igf2 and H19 into parent-specific chromatin loops.

Imprinted genes are expressed from only one of the parental alleles and are marked epigenetically by DNA methylation and histone modifications. The paternally expressed gene insulin-like growth-factor 2 (Igf2) is separated by approximately 100 kb from the maternally expressed noncoding gene H19 on mouse distal chromosome 7. Differentially methylated regions in Igf2 and H19 contain chromatin boundaries, silencers and activators and regulate the reciprocal expression of the two genes in a methylation-sensitive manner by allowing them exclusive access to a shared set of enhancers. Various chromatin models have been proposed that separate Igf2 and H19 into active and silent domains. Here we used a GAL4 knock-in approach as well as the chromosome conformation capture technique to show that the differentially methylated regions in the imprinted genes Igf2 and H19 interact in mice. These interactions are epigenetically regulated and partition maternal and paternal chromatin into distinct loops. This generates a simple epigenetic switch for Igf2 through which it moves between an active and a silent chromatin domain.

Animals↗
PubMed2004

Closed chromatin loops at the ends of chromosomes.

The termini of eukaryotic chromosomes contain specialized protective structures, the telomeres, composed of TTAGGG repeats and associated proteins which, together with telomerase, control telomere length. Telomere shortening is associated with senescence and inappropriate telomerase activity may lead to cancer. Little is known about the chromatin context of telomeres, because, in most cells, telomere chromatin is tightly anchored within the nucleus. We now report the successful release of telomere chromatin from chicken erythrocyte and mouse lymphocyte nuclei, both of which have a reduced karyoskeleton. Electron microscopy reveals telomere chromatin fibers in the form of closed terminal loops, which correspond to the "t-loop" structures adopted by telomere DNA. The ability to recognize isolated telomeres in their native chromatin conformation opens the way for detailed structural and compositional studies.

Animals↗