A Boundary Element Between<i>Tsix</i>and<i>Xist</i>Binds the Chromatin Insulator Ctcf and Contributes to Initiation of X-Chromosome Inactivation

Spencer, Rebecca J.; Rosario, Brian C. Del; Pinter, Stefan F.; Lessing, Derek; Sadreyev, Ruslan I.; Lee, Jeannie T.

doi:10.1534/genetics.111.132662

Cited by 42 publications

(39 citation statements)

References 83 publications

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“…CTCF is found to bind to a conserved sequence element positioned between the Tsix and Xist genes. Depletion of CTCF or deletion of the binding site results in aberrant X inactivation in female cells (Spencer et al, 2011). The interpretation by the authors is that the insulator function ensures the differential activity of these adjacent genes.…”

Section: Embryonic Developmentmentioning

confidence: 98%

CTCF: insights into insulator function during development

2012

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The genome of higher eukaryotes exhibits a patchwork of inactive and active genes. The nuclear protein CCCTC-binding factor (CTCF) when bound to insulator sequences can prevent undesirable crosstalk between active and inactive genomic regions, and it can also shield particular genes from enhancer function, a role that has many applications in development. Exciting recent work has demonstrated roles for CTCF in, for example, embryonic, neuronal and haematopoietic development. Here, we discuss the underlying mechanisms of developmentally regulated CTCF-dependent transcription in relation to model genes, and highlight genome-wide results indicating that CTCF might play a master role in regulating both activating and repressive transcription events at sites throughout the genome. Key words: Igf2/H19, Cohesin, Homeotic gene, Imprint, Insulator IntroductionAs early as the 1950s, the existence of genomic insulators has been postulated based on several observations, such as the phenomenon of position effect variegation (see Glossary, Box 1), in which gene activity is dependent on its genomic location (Lewis, 1950). These locations were later identified as heterochromatic, or inactive, chromatin regions, which, upon translocation, inversion or deletion of chromosomal fragments, may repress the expression of a neighbouring gene (Baker, 1968). The interpretation of this observation was that the genomic rearrangement might have deleted insulators that normally protect genes from the repressive effect of flanking heterochromatin. To add weight to this notion, the biophysical analysis of the Drosophila genome argued for the presence of insulator sequences that separate supercoiled genomic domains (Benyajati and Worcel, 1976). More recently, functional tests with transgenes (see Glossary, Box 1) revealed the existence of three properties of insulators (see Glossary, Box 1): (1) to provide a barrier (or boundary; see Glossary, Box 1) function to prevent repressive heterochromatin from spreading into a neighbouring domain; (2) to provide an enhancer-blocking (see Glossary, Box 1) function when positioned between the enhancer and promoter (see Glossary, Box 1) (Sun and Elgin, 1999), allowing insulators to produce opposite effects either by facilitating the maintenance of a transcriptionally active state or by inhibiting the action of enhancers; (3) to allow three-dimensional looping of genomic regions, a property that is possibly inherent to insulator function, as discussed throughout this review.The first proteins identified that bind to insulator sequences and mediate the insulating function were boundary element-associated factor of 32 kDa (BEAF32) (Zhao et al., 1995), Su(Hw) (Holdridge and Dorsett, 1991;Geyer and Corces, 1992) and zeste-white 5 (Zw5; dwg -FlyBase) (Gaszner et al., 1999) in Drosophila. In vertebrates, CCCTC-binding factor (CTCF) was first shown to mediate insulation (Bell et al., 1999) and was later demonstrated to be highly conserved and also found in Drosophila (dCTCF) (Moon et al., 2005). The DNA-binding do...

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Section: Embryonic Developmentmentioning

confidence: 98%

CTCF: insights into insulator function during development

2012

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“…The sequences deleted in the two studies could be one reason for the phenotype difference, since neither completely abrogates the Rnf12 protein: an 60 Genome architecture and expression Recent evidence implicates autosomal trans-acting factors in Xist regulation (Figure 2), in particular the DNA methyltransferase Dnmt1 [43], the transcription factor YY1, and CTCF, a transcription factor and chromatin insulator. CTCF binds strongly at the boundary between the Xist and Tsix TADs, the deletion of which leads to compromised Xist induction and aberrant XCI [27,44]. CTCF is also thought to promote pairing [45] and repress Xist by binding at its promoter [20].…”

Section: Coupling Chromosome Conformation and Transcription At The Xicmentioning

confidence: 99%

X-chromosome inactivation: new insights into cis and trans regulation

Galupa

Heard

2015

Current Opinion in Genetics & Development

141

137

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“…61,71 CTCF binding sites facilitate interactions within the Tsix TAD 62 and potentially also serve as boundary elements between the Xist and Tsix TADs. 80 Therefore, the coordinated transcriptional control within the opposing Xist and Tsix chromatin domains seems to be achieved at least in part through spatial interactions inside those domains. Further studies of how the TADs relate functionally to the Xic activators and repressors will be of interest and may reveal mechanistic insight into gene regulation via higher order structures.…”

Section: -70mentioning

confidence: 99%

Coupling of X-Chromosome reactivation with the pluripotent stem cell state

Payer

Lee

2014

RNA Biology

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X -chromosome inactivation (XCI)in female mammals is a dramatic example of epigenetic gene regulation, which entails the silencing of an entire chromosome through a wide range of mechanisms involving noncoding RNAs, chromatin-modifications, and DNAmethylation. While XCI is associated with the differentiated cell state, it is reversed by X-chromosome reactivation (XCR) ex vivo in pluripotent stem cells and in vivo in the early mouse embryo and the germline. Critical in the regulation of XCI vs. XCR is the X-inactivation center, a multigene locus on the X-chromosome harboring several long noncoding RNA genes including, most prominently, Xist and Tsix. These genes, which sit at the top of the XCI hierarchy, are by themselves controlled by pluripotency factors, coupling XCR with the naïve pluripotent stem cell state. In this point-of-view article we review the latest findings regarding this intricate relationship between cell differentiation state and epigenetic control of the X-chromosome. In particular, we discuss the emerging picture of complex multifactorial regulatory mechanisms, ensuring both a finetuned and robust X-reactivation process.

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A Boundary Element BetweenTsixandXistBinds the Chromatin Insulator Ctcf and Contributes to Initiation of X-Chromosome Inactivation

Cited by 42 publications

References 83 publications

CTCF: insights into insulator function during development

CTCF: insights into insulator function during development

X-chromosome inactivation: new insights into cis and trans regulation

Coupling of X-Chromosome reactivation with the pluripotent stem cell state

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