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Results for “Chromatin long range interaction”

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PubMed1994

Regulated expression of the beta-globin gene locus in synthetic nuclei.

Regulated gene expression within a complex chromosomal locus requires multiple nuclear processes. We have analyzed the transcriptional properties of the cloned chick beta-globin gene family when assembled into synthetic nuclei made by use of Xenopus egg extracts. Assembly in an erythroid protein environment correctly recapitulates tissue-specific chromatin structure and long-range promoter-enhancer interaction within the chromosomal locus, resulting in beta-globin gene activation. Nucleosome-repressed beta-globin templates can be transcriptionally activated by double-stranded DNA replication in the presence of staged erythroid proteins by remodeling of the chromatin structure within the promoter region and establishment of distal promoter-enhancer communication. The programmed transcriptional state of a gene, as encoded by its chromatin structure and long-range promoter-enhancer interactions, is stable to nuclear decondensation and DNA replication unless active remodeling occurs in the presence of specific DNA-binding proteins.

Animals↗

PubMed2006

Estimating the prevalence and regulatory potential of the telomere looping effect in yeast transcription regulation.

Telomeres have long been implicated in the regulation of gene expression. Some studies have reported that telomere looping effect (TLE) can juxtapose genes and regulatory sequences that are far apart and facilitate long-distance control of gene expression. In this work, we report a detailed investigation on the prevalence and regulatory potential of TLE on a genomic scale by assembling data on protein-DNA interactions from several large-scale ChIp-chip experiments in Saccharomyces cerevisiae. Analysis of the assembled data revealed that a statistically significant number of DNA segments that were inferred to be bound by ten or more transcription factors in these experiments physically mapped to the ends of several chromosomes (19 of 32 chromosome ends). For the 83 transcription factors that were inferred to interact with these DNA segments, we found a statistically significant skew in the distribution of their internal binding sites over the length of the entire chromosome, such that more than expected binding events occurred proximal to chromosomal ends than elsewhere. Taken together these observations suggest that the telomere looping effect is their most likely explanation and imply that a notable fraction of the internally bound yeast transcription factors potentially interact with looped back telomeres. Further, we also identified several components of the basal transcriptional machinery that are also frequently linked to these chromosome end segments, strengthening the proposal for a direct interaction between the chromosome ends and internally located transcriptional complexes. We observed that certain chromatin factors might participate in the TLE and potentially modulate gene expression by chromatin modifications such as histone deacetylation. Our findings provide the first computational evidence for a significant role of long-range regulatory interactions due to telomere looping. Based on these observations, we also propose that genome-wide chromatin immunoprecipitation data might be useful to systematically uncover long-range chromatin looping effects in gene expression.

Binding Sites↗

PubMed2003

Targeted cytosine methylation for in vivo detection of protein-DNA interactions.

We report a technique, named targeted gene methylation (TAGM), for identifying in vivo protein-binding sites in chromatin. M.CviPI, a cytosine-5 DNA methyltransferase recognizing GC sites, is fused to a DNA-binding factor enabling simultaneous detection of targeted methylation, factor footprints, and chromatin structural changes by bisulfite genomic sequencing. Using TAGM with the yeast transactivator Pho4, methylation enrichments of up to 34- fold occur proximal to native Pho4-binding sites. Additionally, significant selective targeting of methylation is observed several hundred nucleotides away, suggesting the detection of long-range interactions due to higher-order chromatin structure. In contrast, at an extragenic locus lacking Pho4-binding sites, methylation levels are at the detection limit at early times after Pho4 transactivation. Notably, substantial amounts of methylation are targeted by Pho4-M.CviPI under repressive conditions when most of the transactivator is excluded from the nucleus. Thus, TAGM enables rapid detection of DNA-protein interactions even at low occupancies and has potential for identifying factor targets at the genome-wide level. Extension of TAGM from yeast to vertebrates, which use methylation to initiate and propagate repressed chromatin, could also provide a valuable strategy for heritable inactivation of gene expression.

Binding Sites↗

PubMed2025

EBV Latency Programs: Molecular and Epigenetic Regulation and Its Role in Disease Pathogenesis.

Epstein-Barr virus (EBV) asymptomatically infects over 95% of the global population, and poses a great threat to human health. This review summarizes the complex mechanisms underlying EBV latency programs and their roles in both viral persistence and disease development. We comprehensively analyze the four distinct latency programs (0, I, II, and III) and their associated gene expression patterns, with particular emphasis on the key viral proteins, the Epstein-Barr virus nuclear antigen EBNA1, EBNA2, EBNA3A/B/C, LMP1, and LMP2A/B. The review explores how these latency programs contribute to various EBV-associated malignancies and autoimmune conditions, including Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, and multiple sclerosis. We detail the multilayered regulation of EBV latency, encompassing epigenetic modifications, chromatin organization, and long-range genomic interactions. Recent advances in understanding the molecular mechanisms of EBV latency maintenance and the virus's interaction with host cellular machinery provide new insights into potential therapeutic approaches for EBV-associated diseases.

Humans↗

PubMed1996

Chromatin: a sticky silence.

Recent findings indicate that heterochromatin serves as a molecular sink for factors involved in chromatin-mediated repression of gene expression; long-range interactions that position a euchromatic gene near a heterochromatin domain influence its susceptibility to transcriptional silencing.

Animals↗

PubMed1999

Locus control regions: coming of age at a decade plus.

The beta-globin locus control region (LCR) is the founding member of a novel class of cis-acting regulatory elements that confer high level, tissue-specific, site-of-integration-independent, copy number-dependent expression on linked transgenes located in ectopic chromatin sites. Knowledge from beta-globin and other LCR studies has shed light on our understanding of the long-range interaction between enhancers and promoters, the relationship between chromatin conformation and transcriptional regulation, and the developmental regulation of multiple gene loci. After over a decade of investigation and discovery, we take a retrospective look at the beta-globin LCR and other LCRs, summarize their properties and review models of LCR function.

Animals↗

PubMed2004

Opening the chromatin for transcription.

Eukaryotic genomes are packaged into a dynamic hierarchy chromatin structure. In such a particular context, the transition from a repressed compacted chromatin to a rather extended fiber is necessary for transcription. The chromatin opening includes three events, the initial factor getting access to nucleosome DNA, local chromatin opening mediated by activator/coactivator, and transcription associated with extensive chromatin opening. Chromatin dynamics, which is DNA sequence dependent, and also occurs in condensed fiber, provides the opportunity for activators binding to DNA. Coactivators recruited by the activator open the chromatin locally. However, it appears that genes adopt distinct chromatin opening mechanisms according to whether the gene is induced expression, developmental and tissue-specific expression, or constitutive expression. In contrast to transcription initiation-related local chromatin opening, large scale of chromatin opening is associated with a functional enhancer as well as high transcription rate. How the transcription initiated from an enhancer or enhancer like modules, i.e. intergenic transcription, conducts the extensive chromatin opening is discussed. A model for long-range interaction that non-coding transcripts from enhancers may promote efficient communication with promoters is proposed.

Animals↗

PubMed2002

Locus control regions.

Locus control regions (LCRs) are operationally defined by their ability to enhance the expression of linked genes to physiological levels in a tissue-specific and copy number-dependent manner at ectopic chromatin sites. Although their composition and locations relative to their cognate genes are different, LCRs have been described in a broad spectrum of mammalian gene systems, suggesting that they play an important role in the control of eukaryotic gene expression. The discovery of the LCR in the beta-globin locus and the characterization of LCRs in other loci reinforces the concept that developmental and cell lineage-specific regulation of gene expression relies not on gene-proximal elements such as promoters, enhancers, and silencers exclusively, but also on long-range interactions of various cis regulatory elements and dynamic chromatin alterations.

Acetylation↗

PubMed2006

SUMO conjugation attenuates the activity of the gypsy chromatin insulator.

Chromatin insulators have been implicated in the establishment of independent gene expression domains and in the nuclear organization of chromatin. Post-translational modification of proteins by Small Ubiquitin-like Modifier (SUMO) has been reported to regulate their activity and subnuclear localization. We present evidence suggesting that two protein components of the gypsy chromatin insulator of Dorsophila melanogaster, Mod(mdg4)2.2 and CP190, are sumoylated, and that SUMO is associated with a subset of genomic insulator sites. Disruption of the SUMO conjugation pathway improves the enhancer-blocking function of a partially active insulator, indicating that SUMO modification acts to regulate negatively the activity of the gypsy insulator. Sumoylation does not affect the ability of CP190 and Mod(mdg4)2.2 to bind chromatin, but instead appears to regulate the nuclear organization of gypsy insulator complexes. The results suggest that long-range interactions of insulator proteins are inhibited by sumoylation and that the establishment of chromatin domains can be regulated by SUMO conjugation.

Animals↗

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↗

PubMed2006

Cooperativeness of the higher chromatin structure of the beta-globin locus revealed by the deletion mutations of DNase I hypersensitive site 3 of the LCR.

High-level transcription of the globin genes requires the enhancement by a distant element, the locus control region (LCR). Such long-range regulation in vivo involves spatial interaction between transcriptional elements, with intervening chromatin looping out. It has been proposed that the clustering of the HS sites of the LCR, the active globin genes, as well as the remote 5' hypersensitive sites (HSs) (HS-60/-62 in mouse, HS-110 in human) and 3'HS1 forms a specific spatial chromatin structure, termed active chromatin hub (ACH). Here we report the effects of the HS3 deletions of the LCR on the spatial chromatin structure of the beta-globin locus as revealed by the chromatin conformation capture (3C) technology. The small HS3 core deletion (0.23 kb), but not the large HS3 deletion (2.3 kb), disrupted the spatial interactions among all the HS sites of the LCR, the beta-globin gene and 3'HS1. We have previously demonstrated that the large HS3 deletion barely impairs the structure of the LCR holocomplex, while the structure is significantly disrupted by the HS3 core deletion. Taken together, these results suggest that the formation of the ACH is dependent on a largely intact LCR structure. We propose that the ACH indeed is an extension of the LCR holocomplex.

Animals↗

PubMed2003

Assessing the role of the T cell receptor beta gene enhancer in regulating coding joint formation during V(D)J recombination.

To assess the role of the T cell receptor (TCR) beta gene enhancer (Ebeta) in regulating the processing of VDJ recombinase-generated coding ends, we assayed TCRbeta rearrangement of Ebeta-deleted (DeltaEbeta) thymocytes in which cell death is inhibited via expression of a Bcl-2 transgene. Compared with DeltaEbeta, DeltaEbeta Bcl-2 thymocytes show a small accumulation of TCRbeta standard recombination products, including coding ends, that involves the proximal Dbeta-Jbeta and Vbeta14 loci but not the distal 5' Vbeta genes. These effects are detectable in double negative pro-T cells, predominate in double positive pre-T cells, and correlate with regional changes in chromosomal structure during double negative-to-double positive differentiation. We propose that Ebeta, by driving long range nucleoprotein interactions and the control of locus expression and chromatin structure, indirectly contributes to the stabilization of coding ends within the recombination processing complexes. The results also illustrate Ebeta-dependent and -independent changes in chromosomal structure, suggesting distinct modes of regulation of TCRbeta allelic exclusion depending on the position within the locus.

Alleles↗

PubMed2026

Loss of SUMOylation drives aberrant PRC1 clustering and 3D genome rewiring independent of H3K27me3.

Polycomb repressive complex 1 (PRC1) forms nuclear condensates that organize target chromatin domains. SUMOylation modulates PRC1 clustering, but its impact on condensate properties and 3D genome architecture remains unclear. Here, we show that depletion of small ubiquitin-like modifier (SUMO) in Drosophila wing imaginal discs transforms PRC1 condensates into large structures with reduced molecular dynamics. Biophysical modeling suggests that the changes in PRC1 self-interactions are responsible for the formation of large PRC1 condensates when SUMO is depleted. Interestingly, this biophysical reorganization occurs without global loss of the H3K27me3 mark. Instead, Hi-C reveals widespread rewiring of topologically associating domain (TAD) interactions. PRC1-bound TADs lose specific long-range contacts with each other while gaining ectopic interactions with active chromatin. These topological shifts correlate with gene misregulation independently of changes in Polycomb histone modifications. Our results establish SUMOylation as a critical regulator of PRC1 condensates, demonstrating that post-translational control of biomolecular condensation modulates 3D genome architecture and transcriptional output through mechanisms separable from histone mark deposition.

Animals↗

PubMed2000

Specification of chromatin domains and regulation of replication and transcription during development.

It is becoming increasingly clear that transcription control is carried out at several interconnecting levels. Besides nucleosomal organization and interaction between transcription factors and gene promoters and other regulatory elements, long-range organization of chromatin in loops or domains seems to play a role in transcriptional regulation. A similar organization is likely to be crucial in the control of the timing and selection of origins of DNA replication. This review considers the implications of domain organization of eukaryotic genome in developmental control of transcription and replication.

Animals↗

PubMed2026

Condensin accelerates long-range intra-chromosomal interactions.

The 3D genome organization plays a key role in regulating interactions among chromosomal loci. While Chromosome Conformation Capture (3C)-based methods have provided static snapshots of chromatin architecture, the kinetics of chromosomal encounters in live cells remain poorly characterized. In this study, we employ Chemically Induced Chromosomal Interaction (CICI) to measure encounter times between multiple loci pairs in G1-arrested budding yeast. Our results show that chromosome motion closely follows the Rouse polymer model, with similar diffusion parameters at all tested loci. Surprisingly, we find that long-range intra-chromosomal encounters occur significantly faster than inter-chromosomal encounters at similar 3D distances. Using targeted depletion experiments, we identify condensin, but not cohesin, as the complex mostly responsible for these rapid intra-chromosomal interactions. This is further supported by Hi-C analysis, which reveals that condensin promotes long-distance intra-chromosomal interactions in G1 yeast. Through polymer simulations, we estimate that condensin extrudes chromatin at ~2 kb/s with a density of one complex per 1-2 Mb and a processivity of 120-220 kb. These findings uncover a novel role for condensin in shaping the interphase genome organization and provide new insights into chromosomal search dynamics in vivo.

Saccharomyces cerevisiae↗

PubMed2001

Multiple regimes of constrained chromosome motion are regulated in the interphase Drosophila nucleus.

BACKGROUND: Increasing evidence indicates specific changes in the three-dimensional organization of chromosomes in the cell nucleus during the cell cycle and development. These changes may be linked to changes in both the coordinated regulation of gene transcription and the timing of chromosome replication. While there is cytological evidence for short-range diffusive motion of chromosomes during interphase, the mechanisms for large-scale chromosome remodeling inside the nucleus remain unknown. RESULTS: Chromosome motion was tracked in Drosophila spermatocyte nuclei by 3D fluorescence microscopy. The Lac repressor/lac operator system was used to label specific chromosomal sites in live tissues, allowing extended observation of chromatin motion in different cell cycle stages. Our results reveal a highly dynamic chromosome organization governed by two types of motion: a fast, short-range component over a 1-2 s time scale and a slower component related to long-range chromosome motion within the nucleus. The motion patterns are consistent with a random walk. In early G2, short-range motion occurs within a small, approximately 0.5 microm radius domain, while long-range motion is confined to a much larger, chromosome-sized domain. Progression through G2 as cells approach meiotic prophase is accompanied by a complete arrest of long-range chromosome motion. CONCLUSIONS: Our analysis provides direct evidence for cell cycle-regulated changes in interphase chromatin motion. These changes are consistent with changes in local and long-range constraints on chromosome motility. We propose that dynamic interactions between chromosomes and internal nuclear structures modulate the range and rate of interphase chromatin diffusion and thereby regulate large-scale nuclear chromosome organization.

Animals↗

PubMed2026

Nuclear exosome targeting complexes modulate cohesin binding and enhancer-promoter interactions in 3D.

Three-dimensional long-range contacts between enhancers and promoters are thought to be largely determined by loop extrusion driven by the cohesin complex and insulator factors. However, recent evidence also suggests a role for noncoding RNAs, such as enhancer-associated RNAs and promoter upstream transcripts, in shaping enhancer-promoter connectivity. While the nuclear RNA exosome, together with targeting complexes, poly(A) tail exosome targeting connection and nuclear exosome targeting complex, controls the decay of noncoding RNAs, it remains unclear whether these complexes regulate three-dimensional chromatin contacts. Chromatin recruitment maps of the nuclear exosome targeting complex subunit ZCCHC8, the poly(A) tail exosome targeting connection subunit ZFC3H1, and the RNA helicase MTR4 in human cells reveal that these factors associate with sites of enhancer-promoter interactions. Depletion of these factors leads to the accumulation of ncRNAs, notably enhancer-associated RNAs and promoter upstream transcripts, and increases cohesin occupancy at these sites. Chromatin conformation capture analysis reveals that MTR4 modulates long-range enhancer-promoter contacts. Upon loss of MTR4, enhancer-promoter contacts increase while intraloop contacts decrease, suggesting that MTR4 facilitates loop extrusion. These data highlight a key interplay between cohesin-mediated enhancer-promoter interactions and the regulation of noncoding RNAs by nuclear RNA exosome targeting complexes that is consistent with a role for RNA in genome folding.

Cohesins↗

PubMed2002

Looping and interaction between hypersensitive sites in the active beta-globin locus.

Eukaryotic transcription can be regulated over tens or even hundreds of kilobases. We show that such long-range gene regulation in vivo involves spatial interactions between transcriptional elements, with intervening chromatin looping out. The spatial organization of a 200 kb region spanning the murine beta-globin locus was analyzed in expressing erythroid and nonexpressing brain tissue. In brain, the globin cluster adopts a seemingly linear conformation. In erythroid cells the hypersensitive sites of the locus control region (LCR), located 40-60 kb away from the active genes, come in close spatial proximity with these genes. The intervening chromatin with inactive globin genes loops out. Moreover, two distant hypersensitive regions participate in these interactions. We propose that clustering of regulatory elements is key to creating and maintaining active chromatin domains and regulating transcription.

Animals↗