Ectopic nuclear reorganisation driven by a<i>Hoxb1</i>transgene transposed into<i>Hoxd</i>

Morey, Céline; Silva, Nelly R. Da; Kmita, Marie; Duboule, Denis; Bickmore, Wendy A.

doi:10.1242/jcs.023234

Cited by 39 publications

(33 citation statements)

References 33 publications

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“…Vice versa, not observing an effect does not exclude that an early act of transcription prior to (drug) treatment was responsible for setting up the 3D structure measured. Nuclear repositioning independent of changes in transcription has been observed before, but only for some individual loci and measured relative to nuclear landmarks like the chromosome territory or nuclear lamina (Morey et al 2008;Peric-Hupkes et al 2010). Our data provide highresolution molecular interaction maps that uncouple topological changes from transcription on a chromosome-wide scale.…”

Section: Transcription and The Shape Of The Inactive X Chromosomesupporting

confidence: 50%

The inactive X chromosome adopts a unique three-dimensional conformation that is dependent on Xist RNA

Splinter

Wit²,

Nora³

et al. 2011

Genes Dev.

289

306

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Three-dimensional topology of DNA in the cell nucleus provides a level of transcription regulation beyond the sequence of the linear DNA. To study the relationship between the transcriptional activity and the spatial environment of a gene, we used allele-specific chromosome conformation capture-on-chip (4C) technology to produce high-resolution topology maps of the active and inactive X chromosomes in female cells. We found that loci on the active X form multiple long-range interactions, with spatial segregation of active and inactive chromatin. On the inactive X, silenced loci lack preferred interactions, suggesting a unique random organization inside the inactive territory. However, escapees, among which is Xist, are engaged in long-range contacts with each other, enabling identification of novel escapees. Deletion of Xist results in partial refolding of the inactive X into a conformation resembling the active X without affecting gene silencing or DNA methylation. Our data point to a role for Xist RNA in shaping the conformation of the inactive X chromosome at least partially independent of transcription.

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Section: Transcription and The Shape Of The Inactive X Chromosomesupporting

confidence: 50%

The inactive X chromosome adopts a unique three-dimensional conformation that is dependent on Xist RNA

Splinter

Wit²,

Nora³

et al. 2011

Genes Dev.

289

306

View full text Add to dashboard Cite

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“…In order to be activated, a gene has to be relocated outside the chromosome territory and its chromatin structure decondensed to a level consistent with the existence of the 30-nm chromatin fiber (35). Poised (potentially active in transcription) and active chromatin domains likely exist in the form of the 30-nm fibers (13 and 37; but also see reference 51).…”

Section: Enhancer Action In Chromatinmentioning

confidence: 99%

“…The simplest, most straightforward model suggests that chromatin-compacted DNA supports efficient EPC. Functionally active genomic regions usually contain E-P spacer DNA that is compacted up to ϳ30-fold into the 30-nm chromatin fiber (35). Therefore, the range of action of the recruiting mechanism could be increased up to 30-fold (to ϳ20-to 30-kb range), provided that the chromatin structure is dynamic.…”

Section: Enhancer Action In Chromatinmentioning

confidence: 99%

Distant Activation of Transcription: Mechanisms of Enhancer Action

Kulaeva

Nizovtseva

Polikanov

et al. 2012

Molecular and Cellular Biology

113

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Enhancers are regulatory DNA sequences that activate transcription over long distances. Recent studies revealed a widespread role of distant activation in eukaryotic gene regulation and in development of various human diseases, including cancer. Genomic and gene-targeted studies of enhancer action revealed novel mechanisms of transcriptional activation over a distance. They include formation of stable, inactive DNA-protein complexes at the enhancer and target promoter before activation, facilitated distant communication by looping of the spacer chromatin-covered DNA, and promoter activation by mechanisms that are different from classic recruiting. These studies suggest the similarity between the looping mechanisms involved in enhancer action on DNA in bacteria and in chromatin of higher organisms. E nhancers (Es) are short (20-to 400-bp) DNA sequences that can activate transcription from target promoters (P) in trans and over various distances (more than 100 kb) (7). Enhancers operate in pro-and eukaryotes; in the majority of cases, action of Es involves direct E-P interaction through proteins bound at the E and P, accompanied by formation of an intervening chromatin loop (7,24,38). Recent genomic studies using various versions of the 3C approach revealed widespread use of gene regulation by enhancers (see reference 32 for a review). In parallel, genomic studies identified specific signatures (histone modifications and associated proteins) of enhancers that greatly facilitated analysis of the databases (32).At the same time, understanding of mechanistic aspects of enhancer action trails behind, primarily due to the lack of in vitro systems faithfully recapitulating distant activation. The enhancer field remains driven by the concept of recruiting that was proposed to explain short-distance activation of transcription in prokaryotes (Fig. 1A) (44). During recruiting, an activator protein increases the local concentration of another protein/protein complex (e.g., RNA polymerase [RNAP]) in the vicinity of its binding site. The local increase of protein concentration results in relief of a step limiting the rate of initiation (usually binding of RNAP to a promoter nearby) and induces transcription. During distant action, even if a protein complex was recruited to the enhancer, its concentration at the target would not necessarily be increased because E/P do not typically colocalize. Furthermore, enhancers typically activate preformed complexes already recruited to DNA ( Fig. 1B; also see below). Thus, the concept of recruiting cannot explain some principal aspects of enhancer action; instead, the presence of preformed enhancer targets raises questions about efficient E-P communication and activation of transcription (Fig. 1B). In this review, we focus primarily on mechanistic aspects of enhancer action; other recent studies were covered in several excellent reviews (7,24,32,38). ENHANCER ACTION ON DNAIn prokaryotes, there are two types of transcriptional enhancers using tracking and looping mechanisms for enhancer-...

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“…This phenomenon, temporal-spatial colinearity, is pivotal for the correct patterning of animal bodies and depends on the proper silencing of 5= HOX genes (1). In a cellular model, a progressive transition from a repressed to an active chromatin state along the cluster from 3= to 5= has been proposed to mediate HOX colinearity (2)(3)(4)(5), accompanied by nuclear reorganization (6)(7)(8)(9) and changes in the higher-order chromatin structure of the clusters (10). A recent study revealed a transition in HOX cluster architecture from an initial single 3-dimensional (3-D) structure to a bimodal state that separates the active and inactive genes during colinear activation of HOX genes in mouse embryos (11).…”

mentioning

confidence: 99%

CTCF Controls HOXA Cluster Silencing and Mediates PRC2-Repressive Higher-Order Chromatin Structure in NT2/D1 Cells

Zhao

et al. 2014

Molecular and Cellular Biology

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dHOX cluster genes are activated sequentially in their positional order along the chromosome during vertebrate development. This phenomenon, known as temporal colinearity, depends on transcriptional silencing of 5= HOX genes. Chromatin looping was recently identified as a conserved feature of silent HOX clusters, with CCCTC-binding factor (CTCF) binding sites located at the loop bases. However, the potential contribution of CTCF to HOX cluster silencing and the underlying mechanism have not been established. Here, we demonstrate that the HOXA locus is organized by CTCF into chromatin loops and that CTCF depletion causes significantly enhanced activation of HOXA3 to -A7, -A9 to -A11, and -A13 in response to retinoic acid, with the highest effect observed for HOXA9. Our subsequent analyses revealed that CTCF facilitates the stabilization of Polycomb repressive complex 2 (PRC2) and trimethylated lysine 27 of histone H3 (H3K27me3) at the human HOXA locus. Our results reveal that CTCF functions as a controller of HOXA cluster silencing and mediates PRC2-repressive higher-order chromatin structure. HOX genes are organized in clusters in vertebrate genomes and are essential for the patterning of the anterior-posterior body axis. These genes are activated in a temporal-spatial manner according to their position along the chromosome in vertebrates. This phenomenon, temporal-spatial colinearity, is pivotal for the correct patterning of animal bodies and depends on the proper silencing of 5= HOX genes (1). In a cellular model, a progressive transition from a repressed to an active chromatin state along the cluster from 3= to 5= has been proposed to mediate HOX colinearity (2-5), accompanied by nuclear reorganization (6-9) and changes in the higher-order chromatin structure of the clusters (10). A recent study revealed a transition in HOX cluster architecture from an initial single 3-dimensional (3-D) structure to a bimodal state that separates the active and inactive genes during colinear activation of HOX genes in mouse embryos (11). Whether spatial chromatin organization is the cause or a consequence of colinear activation and 5= silencing remains unknown. In addition, the factors responsible for the organization of the higher-order chromatin structure of HOX clusters remain to be identified.Recent findings have indicated that CCCTC-binding factor (CTCF) acts as a "master weaver" of the genome (12). Approximately 20,000 CTCF-binding sites (CBSs) have been identified in the human genome (13-15). These sites are frequently associated with cohesin complexes, which mediate sister chromatid cohesion during mitosis and gene regulation in postmitotic cells (16)(17)(18)(19). Multiple highly conserved CBSs have been identified in the human HOXA cluster. Bioinformatics analyses have suggested that CTCF mediates 3-D structure and thereby regulates gene expression in HOX clusters (10). CTCF-binding site 5 in the HOXA cluster (CBS5) has been reported to function as a developmental stage-specific insulator that regulates the expressio...

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Ectopic nuclear reorganisation driven by aHoxb1transgene transposed intoHoxd

Cited by 39 publications

References 33 publications

The inactive X chromosome adopts a unique three-dimensional conformation that is dependent on Xist RNA

The inactive X chromosome adopts a unique three-dimensional conformation that is dependent on Xist RNA

Distant Activation of Transcription: Mechanisms of Enhancer Action

CTCF Controls HOXA Cluster Silencing and Mediates PRC2-Repressive Higher-Order Chromatin Structure in NT2/D1 Cells

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