Cohesin mediates transcriptional insulation by CCCTC-binding factor

Wendt, Kerstin S.; Yoshida, Koshi; Itoh, Takehiko; Bando, Masashige; Koch, Birgit; Schirghuber, Erika; Tsutsumi, Sadami; Nagae, Genta; Ishihara, Kazuhíko; Mishiro, Tsuyoshi; Yahata, Kazuhide; Imamoto, Fumio; Aburatani, Hiroyuki; Nakao, Mitsuyoshi; Imamoto, Naoko; Maeshima, Kazuhiro; Shirahige, Katsuhiko; Peters, Jan Michael

doi:10.1038/nature06634

Cited by 1,086 publications

(1,300 citation statements)

References 53 publications

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“…Furthermore, hSNF2h is important for human cohesin recruitment to a type of Alu repeat sequence, whereas Mre11-Rad50 recruits cohesin to DNA damage sites (Hakimi et al, 2002;Kim et al, 2002). CCCTC-binding factor (CTCF) was also shown to target cohesin to many of the CTCF-binding sites in mammalian cells (Parelho et al, 2008;Stedman et al, 2008;Wendt et al, 2008). Our results reveal that cohesin is recruited to the spindle poles in a mitosis-specific manner through two mechanisms: interaction with centrosomes or with NuMA.…”

Section: Two Distinct Functions Of Cohesin In Mitosismentioning

confidence: 76%

Cohesin Associates with Spindle Poles in a Mitosis-specific Manner and Functions in Spindle Assembly in Vertebrate Cells

Kong

Ball

Sonoda

et al. 2009

MBoC

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Cohesin is an essential protein complex required for sister chromatid cohesion. Cohesin associates with chromosomes and establishes sister chromatid cohesion during interphase. During metaphase, a small amount of cohesin remains at the chromosome-pairing domain, mainly at the centromeres, whereas the majority of cohesin resides in the cytoplasm, where its functions remain unclear. We describe the mitosis-specific recruitment of cohesin to the spindle poles through its association with centrosomes and interaction with nuclear mitotic apparatus protein (NuMA). Overexpression of NuMA enhances cohesin accumulation at spindle poles. Although transient cohesin depletion does not lead to visible impairment of normal spindle formation, recovery from nocodazole-induced spindle disruption was significantly impaired. Importantly, selective blocking of cohesin localization to centromeres, which disrupts centromeric sister chromatid cohesion, had no effect on this spindle reassembly process, clearly separating the roles of cohesin at kinetochores and spindle poles. In vitro, chromosome-independent spindle assembly using mitotic extracts was compromised by cohesin depletion, and it was rescued by addition of cohesin that was isolated from mitotic, but not S phase, cells. The combined results identify a novel spindle-associated role for human cohesin during mitosis, in addition to its function at the centromere/kinetochore regions. INTRODUCTIONMitotic spindle formation is critical for proper chromosome congression, alignment, and segregation during cell division (Compton, 2000;Scholey et al., 2003;Kline-Smith and Walczak, 2004). Microtubules (MTs) undergo drastic changes in their dynamics and organization as the cell enters mitosis to form the bipolar spindle apparatus. As the nuclear membrane breaks down at the G2/M transition, interphase cytoskeletal MTs are destabilized, and mitotic spindle MTs nucleate from two opposing centrosomes/spindle poles with increased growth and turnover rates (Saxton et al., 1984;Zhai et al., 1996). This mitosis-specific change of microtubule behavior indicates the presence of cell cycle-specific regulators of spindles. Indeed, studies identified many important microtubule-associated proteins (MAPs) that regulate different aspects of mitotic spindle dynamics, such as the efficiency of MT nucleation and minus-end focusing at spindle poles, MT plus-and minus-end dynamics, and overall spindle stability (Kline-Smith and Walczak, 2004). However, the intricate regulatory mechanisms for spindle organization are not completely understood, and there are most likely additional factors that contribute to proper spindle regulation during mitosis.Cohesin is a conserved and essential multiprotein complex required for sister chromatid cohesion (Losada et al., 1998;Uhlmann and Nasmyth, 1998;Toth et al., 1999). Genetic studies in both yeast and metazoans revealed that inhibition of cohesin function leads to premature separation of sister chromatids, chromosome misalignment, and meloteric attachment of spindles to...

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Section: Two Distinct Functions Of Cohesin In Mitosismentioning

confidence: 76%

Cohesin Associates with Spindle Poles in a Mitosis-specific Manner and Functions in Spindle Assembly in Vertebrate Cells

Kong

Ball

Sonoda

et al. 2009

MBoC

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“…32 Cohesin is recruited to chromatin through its interaction with DNA-binding proteins, including the CCCTCF binding factor (CTCF). 33 It co-occupies up to 90% of CTCF binding sites, 33,34 and some functions initially attributed to CTCF may depend on cohesin. 34 The cohesin-CTCF complex, which assembles in a cell-cycle-dependant 35 and developmentally-regulated 36 manner, can recruit RNA polymerase II to directly promote transcription, 37 and form DNA loop structures to mediate transcriptional insulation 31,34 or connect enhancers with core promoters.…”

Section: Discussionmentioning

confidence: 99%

“…33 It co-occupies up to 90% of CTCF binding sites, 33,34 and some functions initially attributed to CTCF may depend on cohesin. 34 The cohesin-CTCF complex, which assembles in a cell-cycle-dependant 35 and developmentally-regulated 36 manner, can recruit RNA polymerase II to directly promote transcription, 37 and form DNA loop structures to mediate transcriptional insulation 31,34 or connect enhancers with core promoters. 25 Complexed with various other transcription factors, cohesin mediates tissue-specific 30,33 and hormone responsive transcription, 33 as well as the coordinated expression of genes with interrelated functions 38 and multiple genes in clusters.…”

Section: Discussionmentioning

confidence: 99%

Familial skewed X-chromosome inactivation linked to a component of the cohesin complex, SA2

et al. 2011

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The gene dosage inequality between females with two X-chromosomes and males with one is compensated for by X-chromosome inactivation (XCI), which ensures the silencing of one X in every somatic cell of female mammals. XCI in humans results in a mosaic of two cell populations: those expressing the maternal X-chromosome and those expressing the paternal X-chromosome. We have previously shown that the degree of mosaicism (the X-inactivation pattern) in a Canadian family is directly related to disease severity in female carriers of the X-linked recessive bleeding disorder, haemophilia A. The distribution of X-inactivation patterns in this family was consistent with a genetic trait having a co-dominant mode of inheritance, suggesting that XCI choice may not be completely random. To identify genetic elements that could be responsible for biased XCI choice, a linkage analysis was undertaken using an approach tailored to accommodate the continuous nature of the X-inactivation pattern phenotype in the Canadian family. Several X-linked regions were identified, one of which overlaps with a region previously found to be linked to familial skewed XCI. SA2, a component of the cohesin complex is identified as a candidate gene that could participate in XCI through its association with CTCF.

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“…Furthermore, it was found recently that cohesin and CTCF-binding sites have a high degree of overlap, and interacts with each other. 20,[22][23][24] Moreover, often cohesin and CTCF have been found to colocalize at several thousand sites in non-repetitive sequences in the human genome. 22,24,25 In addition to the regulation of gene expression, cohesin has also other important functions: it forms a huge tripartite ring, mediates the sister chromatid cohesion, and facilitates the repair of damaged DNA.…”

Section: Gene Expression and Iq In Trisomy 21mentioning

confidence: 99%

“…20,[22][23][24] Moreover, often cohesin and CTCF have been found to colocalize at several thousand sites in non-repetitive sequences in the human genome. 22,24,25 In addition to the regulation of gene expression, cohesin has also other important functions: it forms a huge tripartite ring, mediates the sister chromatid cohesion, and facilitates the repair of damaged DNA. 26,27 From our analysis, we can postulate that HLA-DQA1 and HLA-DRB1 may represent a genetic biomarker for predicting differences in ID conditions, but also that polymorphisms or mutations of the cohesin subunits might have an important role for the non-disjunction of the chromosomes 21 and/or for the dysregulation of the expression of many genes.…”

Section: Gene Expression and Iq In Trisomy 21mentioning

confidence: 99%

The intellectual disability of trisomy 21: differences in gene expression in a case series of patients with lower and higher IQ

Mégarbané

Noguier²,

Stora

et al. 2013

Eur J Hum Genet

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Trisomy 21 (T21), or Down syndrome (DS), is the most frequent and recognizable cause of intellectual disabilities. The level of disability, as evaluated by the intelligence quotient (IQ) test, varies considerably between patients independent of other factors. To determine the genetic or molecular basis of this difference, a high throughput transcriptomic analysis was performed on twenty T21 patients with high and low IQ, and 10 healthy controls using Digital Gene Expression. More than 90 millions of tags were sequenced in the three libraries. A total of 80 genes of potential interest were selected for the qPCR experiment validation, and three housekeeping genes were used for normalizing purposes. HLA DQA1 and HLA DRB1 were significantly downregulated among the patients with a low IQ, the values found in the healthy controls being intermediate between those noted in the IQ þ and IQ À T21 patients. Interestingly, the intergenic region between these genes contains a binding sequence for the CCCTC-binding factor, or CTCF, and cohesin (a multisubunit complex), both of which are essential for expression of HLA DQA1 and HLA DRB1 and numerous other genes. Our results might lead to the discovery of genes, or genetic markers, that are directly involved in several phenotypes of DS and, eventually, to the identification of potential targets for therapeutic interventions.

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Cohesin mediates transcriptional insulation by CCCTC-binding factor

Cited by 1,086 publications

References 53 publications

Cohesin Associates with Spindle Poles in a Mitosis-specific Manner and Functions in Spindle Assembly in Vertebrate Cells

Cohesin Associates with Spindle Poles in a Mitosis-specific Manner and Functions in Spindle Assembly in Vertebrate Cells

Familial skewed X-chromosome inactivation linked to a component of the cohesin complex, SA2

The intellectual disability of trisomy 21: differences in gene expression in a case series of patients with lower and higher IQ

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