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In eukaryotic genome biology, the genomic organization inside the three-dimensional(3 D) nucleus is highly complex, and whether this organization governs gene expression is poorly understood. Nuclear lamina(NL)is a filamentous meshwork of proteins present at the lining of inner nuclear membrane that serves as an anchoring platform for genome organization. Large chromatin domains termed as lamina-associated domains(LADs), play a major role in silencing genes at the nuclear periphery. The interaction of the NL and genome is dynamic and stochastic. Furthermore, many genes change their positions during developmental processes or under disease conditions such as cancer, to activate certain sorts of genes and/or silence others. Pericentromeric heterochromatin(PCH) is mostly in the silenced region within the genome, which localizes at the nuclear periphery. Studies show that several genes located at the PCH are aberrantly expressed in cancer. The interesting question is that despite being localized in the pericentromeric region,how these genes still manage to overcome pericentromeric repression. Although epigenetic mechanisms control the expression of the pericentromeric region, recent studies about genome organization and genome-nuclear lamina interaction have shed light on a new aspect of pericentromeric gene regulation through a complex and coordinated interplay between epigenomic remodeling and genomic organization in cancer. 相似文献
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The suppressor of Hairy-wing [SU(HW)] binding region disrupts communication between a large number of enhancers and promoters and protects transgenes from chromosomal position effects. These properties classify the SU(HW) binding region as an insulator. While enhancers are blocked in a general manner, protection from repressors appears to be more variable. In these studies, we address whether repression resulting from the Polycomb group genes can be blocked by the SU(HW) binding region. The effects of this binding region on repression established by an Ultrabithorax Polycomb group Response Element were examined. A transposon carrying two reporter genes, the yellow and white genes, was used so that repression and insulation could be assayed simultaneously. We demonstrate that the SU(HW) binding region is effective at preventing Polycomb group repression. These studies suggest that one role of the su(Hw) protein may be to restrict the range of action of repressors, such as the Polycomb group proteins, throughout the euchromatic regions of the genome. 相似文献
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Mutation of a single CTCF target site within the H19 imprinting control region leads to loss of Igf2 imprinting and complex patterns of de novo methylation upon maternal inheritance 总被引:2,自引:0,他引:2
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Pant V Kurukuti S Pugacheva E Shamsuddin S Mariano P Renkawitz R Klenova E Lobanenkov V Ohlsson R 《Molecular and cellular biology》2004,24(8):3497-3504
The differentially methylated imprinting control region (ICR) region upstream of the H19 gene regulates allelic Igf2 expression by means of a methylation-sensitive chromatin insulator function. We have previously shown that maternal inheritance of mutated (three of the four) target sites for the 11-zinc finger protein CTCF leads to loss of Igf2 imprinting. Here we show that a mutation in only CTCF site 4 also leads to robust activation of the maternal Igf2 allele despite a noticeably weaker interaction in vitro of site 4 DNA with CTCF compared to other ICR sites, sites 1 and 3. Moreover, maternally inherited sites 1 to 3 become de novo methylated in complex patterns in subpopulations of liver and heart cells with a mutated site 4, suggesting that the methylation privilege status of the maternal H19 ICR allele requires an interdependence between all four CTCF sites. In support of this conclusion, we show that CTCF molecules bind to each other both in vivo and in vitro, and we demonstrate strong interaction between two CTCF-DNA complexes, preassembled in vitro with sites 3 and 4. We propose that the CTCF sites may cooperate to jointly maintain both methylation-free status and insulator properties of the maternal H19 ICR allele. Considering many other CTCF targets, we propose that site-specific interactions between various DNA-bound CTCF molecules may provide general focal points in the organization of looped chromatin domains involved in gene regulation. 相似文献
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Giorgio Bernardi 《BioEssays : news and reviews in molecular, cellular and developmental biology》2019,41(12)
Recent investigations have revealed 1) that the isochores of the human genome group into two super‐families characterized by two different long‐range 3D structures, and 2) that these structures, essentially based on the distribution and topology of short sequences, mold primary chromatin domains (and define nucleosome binding). More specifically, GC‐poor, gene‐poor isochores are low‐heterogeneity sequences with oligo‐A spikes that mold the lamina‐associated domains (LADs), whereas GC‐rich, gene‐rich isochores are characterized by single or multiple GC peaks that mold the topologically associating domains (TADs). The formation of these “primary TADs” may be followed by extrusion under the action of cohesin and CTCF. Finally, the genomic code, which is responsible for the pervasive encoding and molding of primary chromatin domains (LADs and primary TADs, namely the “gene spaces”/“spatial compartments”) resolves the longstanding problems of “non‐coding DNA,” “junk DNA,” and “selfish DNA” leading to a new vision of the genome as shaped by DNA sequences. 相似文献
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Xiaochun Ni Yong E. Zhang Nicolas N��gre Sidi Chen Manyuan Long Kevin P. White 《PLoS biology》2012,10(11)
Changes in the physical interaction between cis-regulatory DNA sequences and proteins drive the evolution of gene expression. However, it has proven difficult to accurately quantify evolutionary rates of such binding change or to estimate the relative effects of selection and drift in shaping the binding evolution. Here we examine the genome-wide binding of CTCF in four species of Drosophila separated by between ∼2.5 and 25 million years. CTCF is a highly conserved protein known to be associated with insulator sequences in the genomes of human and Drosophila. Although the binding preference for CTCF is highly conserved, we find that CTCF binding itself is highly evolutionarily dynamic and has adaptively evolved. Between species, binding divergence increased linearly with evolutionary distance, and CTCF binding profiles are diverging rapidly at the rate of 2.22% per million years (Myr). At least 89 new CTCF binding sites have originated in the Drosophila melanogaster genome since the most recent common ancestor with Drosophila simulans. Comparing these data to genome sequence data from 37 different strains of Drosophila melanogaster, we detected signatures of selection in both newly gained and evolutionarily conserved binding sites. Newly evolved CTCF binding sites show a significantly stronger signature for positive selection than older sites. Comparative gene expression profiling revealed that expression divergence of genes adjacent to CTCF binding site is significantly associated with the gain and loss of CTCF binding. Further, the birth of new genes is associated with the birth of new CTCF binding sites. Our data indicate that binding of Drosophila CTCF protein has evolved under natural selection, and CTCF binding evolution has shaped both the evolution of gene expression and genome evolution during the birth of new genes. 相似文献
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CTCF plays a central role in vertebrate insulators and forms part of the Fab-8 insulator in Drosophila. dCTCF is present at hundreds of sites in the Drosophila genome, where it is located at the boundaries between bands and interbands in polytene chromosomes. dCTCF colocalizes with CP190, which is required for proper binding of dCTCF to chromatin, but not with the other gypsy insulator proteins Su(Hw) or Mod(mdg4)2.2. Mutations in the CP190 gene affect Fab-8 insulator activity, suggesting that CP190 is an essential component of both gypsy and dCTCF insulators. dCTCF is present at specific nuclear locations, forming large insulator bodies that overlap with those formed by Su(Hw), Mod(mdg4)2.2, and CP190. The results suggest that Su(Hw) and dCTCF may be the DNA-binding components of two different subsets of insulators that share CP190 and cooperate in the formation of insulator bodies to regulate the organization of the chromatin fiber in the nucleus. 相似文献
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Monica Guidi Margarita Muiños-Gimeno Birgit Kagerbauer Eulàlia Martí Xavier Estivill Yolanda Espinosa-Parrilla 《BMC molecular biology》2010,11(1):1-17