Transcriptional Dysregulation in NIPBL and Cohesin Mutant Human Cells

Liu, Jinglan; Zhang, Zhe; Bando, Masashige; Itoh, Takehiko; Deardorff, Matthew A.; Clark, Dinah; Kaur, Maninder; Tandy, Stephany; Kondoh, Tatsuro; Rappaport, Eric; Spinner, Nancy B.; Vega, Hugo Gutiérrez; Jackson, Laird G.; Shirahige, Katsuhiko; Krantz, Ian D.

doi:10.1371/journal.pbio.1000119

Cited by 208 publications

(347 citation statements)

References 59 publications

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“…It may be that it has little part in the role that NIPBL has in chromatin reorganization or transcriptional regulation, a role largely speculated to be the predominant defect in CdLS. 28,33,49 It has yet to be defined whether these additional functions of NIPBL utilize MAU2.…”

Section: Clinical Features Of Patientsmentioning

confidence: 99%

Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction

et al. 2011

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Cornelia de Lange syndrome (CdLS; or Brachmann-de Lange syndrome) is a dominantly inherited congenital malformation disorder with features that include characteristic facies, cognitive delays, growth retardation and limb anomalies. Mutations in nearly 60% of CdLS patients have been identified in NIPBL, which encodes a regulator of the sister chromatid cohesion complex. NIPBL, also known as delangin, is a homolog of yeast and amphibian Scc2 and C. elegans PQN-85. Although the exact mechanism of NIPBL function in sister chromatid cohesion is unclear, in vivo yeast and C. elegans experiments and in vitro vertebrate cell experiments have demonstrated that NIPBL/Scc2 functionally interacts with the MAU2/Scc4 protein to initiate loading of cohesin onto chromatin. To test the significance of this model in the clinical setting of CdLS, we fine-mapped the NIPBL-MAU2 interaction domain and tested the functional significance of missense mutations and variants in NIPBL and MAU2 identified in these minimal domains in a cohort of patients with CdLS. We demonstrate that specific novel mutations at the N-terminus of the MAU2-interacting domain of NIPBL result in markedly reduced MAU2 binding, although we appreciate no consistent clinical difference in the small group of patients with these mutations. These data suggest that factors in addition to MAU2 are essential in determining the clinical features and severity of CdLS.

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Section: Clinical Features Of Patientsmentioning

confidence: 99%

Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction

et al. 2011

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“…The cohesin protein complex is involved in maintaining sister chromatid proximity in dividing cells and has recently been implicated in mediating transcriptional insulation and control via interactions with CTCF (23). siRNA targeting RAD21 (24), SMC3, and NIPBL (25), caused 4OHT and ICI182,780 resistance (Figs. 2B and 3B).…”

Section: Resultsmentioning

confidence: 99%

Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen

Mendes-Pereira

Sims

Dexter

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

119

125

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Therapies that target estrogen signaling have made a very considerable contribution to reducing mortality from breast cancer. However, resistance to tamoxifen remains a major clinical problem. Here we have used a genome-wide functional profiling approach to identify multiple genes that confer resistance or sensitivity to tamoxifen. Combining whole-genome shRNA screening with massively parallel sequencing, we have profiled the impact of more than 56,670 RNA interference reagents targeting 16,487 genes on the cellular response to tamoxifen. This screen, along with subsequent validation experiments, identifies a compendium of genes whose silencing causes tamoxifen resistance (including BAP1 , CLPP , GPRC5D , NAE1 , NF1 , NIPBL , NSD1 , RAD21 , RARG , SMC3 , and UBA3 ) and also a set of genes whose silencing causes sensitivity to this endocrine agent ( C10orf72 , C15orf55/NUT , EDF1 , ING5 , KRAS , NOC3L , PPP1R15B , RRAS2 , TMPRSS2 , and TPM4 ). Multiple individual genes, including NF1 , a regulator of RAS signaling, also correlate with clinical outcome after tamoxifen treatment.

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“…Recent studies in which one or a few specific CTCF sites were lost due to deletion or mutation have revealed both positive and negative effects on transcription of local genes (8,21,28,29). However, deletion of the mouse β-globin HS5 and 3′HS1 CTCF sites individually or in combination did not affect β-globin gene expression, suggesting that, although these sites interact in vivo, they are not required to function as insulators at their endogenous location in the mouse genome (30)(31)(32).…”

Section: Ctcf Reduction Alters the Epigenetic Environment Within Thementioning

confidence: 99%

Cell type specificity of chromatin organization mediated by CTCF and cohesin

Hou

Dale

Dean

2010

Proc. Natl. Acad. Sci. U.S.A.

229

214

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CTCF sites are abundant in the genomes of diverse species but their function is enigmatic. We used chromosome conformation capture to determine long-range interactions among CTCF/cohesin sites over 2 Mb on human chromosome 11 encompassing the β-globin locus and flanking olfactory receptor genes. Although CTCF occupies these sites in both erythroid K562 cells and fibroblast 293T cells, the long-range interaction frequencies among the sites are highly cell type specific, revealing a more densely clustered organization in the absence of globin gene activity. Both CTCF and cohesins are required for the cell-type-specific chromatin conformation. Furthermore, loss of the organizational loops in K562 cells through reduction of CTCF with shRNA results in acquisition of repressive histone marks in the globin locus and reduces globin gene expression whereas silent flanking olfactory receptor genes are unaffected. These results support a genome-wide role for CTCF/cohesin sites through loop formation that both influences transcription and contributes to cell-type-specific chromatin organization and function.chromatin loops | insulator | CTCF | globin | transcription E ukaryotic chromatin is dynamically organized to form distinct transcriptionally active or silent domains (1). Chromatin insulators are proposed to play a role in the establishment of such domains within which proper enhancer-gene interactions occur and improper ones are excluded (2). Insulators can function as boundary elements between active and silent chromatin domains and can also interfere with enhancer-gene interaction when placed between them. Evidence also suggests that insulators are involved in higher-order chromatin organization by clustering together with other insulators. Such "insulator bodies" can be visualized at the nuclear periphery of certain cells in Drosophila and are thought to coalesce through the interaction of proteins such as Su(Hw) and Drosophila CTCF (3, 4).In mammalian cells, insulators are bound by CTCF, a protein with 11 zinc fingers through which it can bind to a range of DNA sequences, to itself, and to nuclear structural proteins such as nucleophosmin and matrix attachment regions (MARs) (2). Although insulators would be expected to reside primarily in intergenic regions where they could provide boundary or enhancer blocking activity, genome scans of CTCF enrichment show that CTCF sites are overrepresented in genes and promoter regions, with only 41-56% at intergenic locations (5). In Drosophila, between about 49% and 64% of insulator sites are located in intergenic regions (4). Thus, although CTCF sites are proposed to be insulators, their in vivo functions may not be limited to insulation. Recently, cohesin has been reported to colocalize at most sites of CTCF enrichment and to play a role in transcriptional insulation, but the significance of this joint occupancy to higher-order chromatin structures is unknown (6).In the Igf2/H19 locus, CTCF binding to the imprinting control region on the maternal allele is required to loop ...

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Transcriptional Dysregulation in NIPBL and Cohesin Mutant Human Cells

Abstract: Genome-wide studies using cells from patients with Cornelia de Lange Syndrome reveal a role for cohesin in regulating gene expression in human cells.

Cited by 208 publications

References 59 publications

Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction

Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction

Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen

Cell type specificity of chromatin organization mediated by CTCF and cohesin

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