The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Shimako Kawauchi - One of the best experts on this subject based on the ideXlab platform.
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the effect of nipped b like NIPBL haploinsufficiency on genome wide cohesin binding and target gene expression modeling cornelia de lange syndrome
Clinical Epigenetics, 2017Co-Authors: Daniel A Newkirk, Yenyun Chen, Richard Chien, Weihua Zeng, Jacob Biesinger, Ebony Flowers, Shimako KawauchiAbstract:Background Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder frequently associated with heterozygous loss-of-function mutations of Nipped-B-like (NIPBL), the human homolog of Drosophila Nipped-B. NIPBL loads cohesin onto chromatin. Cohesin mediates sister chromatid cohesion important for mitosis but is also increasingly recognized as a regulator of gene expression. In CdLS patient cells and animal models, expression changes of multiple genes with little or no sister chromatid cohesion defect suggests that disruption of gene regulation underlies this disorder. However, the effect of NIPBL haploinsufficiency on cohesin binding, and how this relates to the clinical presentation of CdLS, has not been fully investigated. NIPBL haploinsufficiency causes CdLS-like phenotype in mice. We examined genome-wide cohesin binding and its relationship to gene expression using mouse embryonic fibroblasts (MEFs) from NIPBL+/− mice that recapitulate the CdLS phenotype.
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the effect of nipped b like NIPBL haploinsufficiency on genome wide cohesin binding and target gene expression modeling cornelia de lange syndrome
Clinical Epigenetics, 2017Co-Authors: Daniel A Newkirk, Yenyun Chen, Richard Chien, Weihua Zeng, Jacob Biesinger, Ebony Flowers, Shimako KawauchiAbstract:Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder frequently associated with heterozygous loss-of-function mutations of Nipped-B-like (NIPBL), the human homolog of Drosophila Nipped-B. NIPBL loads cohesin onto chromatin. Cohesin mediates sister chromatid cohesion important for mitosis but is also increasingly recognized as a regulator of gene expression. In CdLS patient cells and animal models, expression changes of multiple genes with little or no sister chromatid cohesion defect suggests that disruption of gene regulation underlies this disorder. However, the effect of NIPBL haploinsufficiency on cohesin binding, and how this relates to the clinical presentation of CdLS, has not been fully investigated. NIPBL haploinsufficiency causes CdLS-like phenotype in mice. We examined genome-wide cohesin binding and its relationship to gene expression using mouse embryonic fibroblasts (MEFs) from NIPBL+/− mice that recapitulate the CdLS phenotype. We found a global decrease in cohesin binding, including at CCCTC-binding factor (CTCF) binding sites and repeat regions. Cohesin-bound genes were found to be enriched for histone H3 lysine 4 trimethylation (H3K4me3) at their promoters; were disproportionately downregulated in NIPBL mutant MEFs; and displayed evidence of reduced promoter-enhancer interaction. The results suggest that gene activation is the primary cohesin function sensitive to NIPBL reduction. Over 50% of significantly dysregulated transcripts in mutant MEFs come from cohesin target genes, including genes involved in adipogenesis that have been implicated in contributing to the CdLS phenotype. Decreased cohesin binding at the gene regions is directly linked to disease-specific expression changes. Taken together, our NIPBL haploinsufficiency model allows us to analyze the dosage effect of cohesin loading on CdLS development.
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the effect of nipped b like NIPBL haploinsufficiency on genome wide cohesin binding and target gene expression modeling cornelia de lange syndrome
bioRxiv, 2017Co-Authors: Daniel A Newkirk, Anne L. Calof, Yenyun Chen, Richard Chien, Weihua Zeng, Jacob Biesinger, Ebony Flowers, Shimako Kawauchi, Rosaysela Santos, Arthur D. LanderAbstract:Cornelia de Lange Syndrome (CdLS) is a multisystem developmental disorder frequently associated with heterozygous loss-of-function mutations of Nipped-B-like (NIPBL), the human homolog of Drosophila Nipped-B. NIPBL loads cohesin onto chromatin. Cohesin mediates sister chromatid cohesion important for mitosis, but is also increasingly recognized as a regulator of gene expression. In CdLS patient cells and animal models, the presence of multiple gene expression changes with little or no sister chromatid cohesion defect suggests that disruption of gene regulation underlies this disorder. However, the effect of NIPBL haploinsufficiency on cohesin binding, and how this relates to the clinical presentation of CdLS, has not been fully investigated. NIPBL haploinsufficiency causes CdLS-like phenotype in mice. We examined genome-wide cohesin binding and its relationship to gene expression using mouse embryonic fibroblasts (MEFs) from NIPBL +/- mice that recapitulate the CdLS phenotype. We found a global decrease in cohesin binding, including at CCCTC-binding factor (CTCF) binding sites and repeat regions. Cohesin-bound genes were found to be enriched for histone H3 lysine 4 trimethylation (H3K4me3) at their promoters; were disproportionately downregulated in NIPBL mutant MEFs; and displayed evidence of reduced promoter-enhancer interaction. The results suggest that gene activation is the primary cohesin function sensitive to NIPBL reduction. Over 50% of significantly dysregulated transcripts in mutant MEFs come from cohesin target genes, including genes involved in adipogenesis that have been implicated in contributing to the CdLS phenotype. Thus, decreased cohesin binding at the gene regions directly contributes to disease-specific expression changes. Taken together, our NIPBL haploinsufficiency model allows us to analyze the dosage effect of cohesin loading on CdLS development.
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Haploinsufficiency for Nkx2-5 increases the incidence and severity of heart defects in NIPBL-deficient embryos.
2016Co-Authors: Rosaysela Santos, Martha E. Lopez-burks, Shimako Kawauchi, Russell E. Jacobs, Hojae Choi, Jamie Wikenheiser, Benedikt Hallgrimsson, Heather A. Jamniczky, Scott E. Fraser, Arthur D. LanderAbstract:A. NIPBL+/-;Nkx2-5+/- mice displayed ASDs (yellow arrowhead), VSDs (green arrowhead), and/or PTAs (black asterisk). B. Histogram showing increases in frequency and types of heart defects in NIPBL+/-;Nkx2-5+/- hearts compared to littermates of various genotypes; number of hearts observed with each type of defect is indicated. Data show that the overall incidence of defects in NIPBL+/-;Nkx2-5+/- hearts (83%) is significantly greater than in either NIPBL+/- (30%, p = 0.011 by Chi square) or Nkx2.5+/- (13%, p = 0.001 by Chi-square) hearts. C. Gross overview of the great vessels highlighting PTA in NIPBL+/-;Nkx2-5+/- mice. D. Heart position and morphology in a subset of NIPBL+/-;Nkx2-5+/- mice was drastically different than in littermates. Arrows indicate the position of the trachea (Tr), dotted lines originate at the pulmonary artery and ends at the apex of the heart; note drastic change in the angle of dotted line in NIPBL+/-;Nkx2-5+/- heart. E. Ventricular volumes for hearts of each genotype; horizontal bars indicate means. Ventricular volumes of NIPBL+/-;Nkx2-5+/- hearts (n = 6) were similar in size to NIPBL+/- hearts (n = 5) (Mann-Whitney U, p > 0.05), whereas control hearts (wildtype n = 5 and Nkx2-5+/-, n = 5) were significantly larger than the hearts of their NIPBL+/- and NIPBL+/-;Nkx2-5+/- littermates (red asterisks: Mann-Whitney U, p < 0.05). ao, aorta; ASD, atrial septal defect; la, left atrium; lv, left ventricle; pa, pulmonary artery; PTA, persistent truncus arteriosus; ra, right atrium; rv, right ventricle; Tr, trachea; VSD, ventricular septal defect; Size bar = 500 μm.
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FLEX alleles allow successive toggling between mutant and wildtype genotypes and phenotypes.
2016Co-Authors: Rosaysela Santos, Martha E. Lopez-burks, Shimako Kawauchi, Russell E. Jacobs, Hojae Choi, Jamie Wikenheiser, Benedikt Hallgrimsson, Heather A. Jamniczky, Scott E. Fraser, Arthur D. LanderAbstract:A. Schematic of EUCE313f02 (NIPBLFLEX) allele from which the NIPBLFLEX/+ mouse line and allelic series are derived. The rsFlp-Rosa-βgeo cassette is inserted 14.5 kbp downstream of NIPBL Exon 1 on Chromosome 15. B. In the NIPBLFLEX allele, the splice acceptor (SA) in the cassette traps NIPBL expression, resulting in termination of NIPBL expression after exon 1 and expression of the β-geo reporter for the trapped null allele. Adult NIPBLFLEX/+ mice are smaller than wildtype littermates: Image is of 4-wk-old male littermates. Scatter plot shows weights of 12-wk-old NIPBLFLEX/+ mice (red, n = 3: 1 female, 2 males) and wildtype littermates (black, n = 8: 4 females, 4 males) from 3 litters. Ubiquitous expression of β-geo was detected by X-gal staining in E10.5 NIPBLFLEX/+ embryos. Histogram shows mean ± SEM of relative NIPBL expression, assessed by qRT-PCR, in kidneys of E17.5 NIPBLFLEX/+ (n = 8) and wildtype littermates (n = 6); asterisk: p < 0.05 by Student’s t test. C. Mating NIPBLFLEX/+ mice with mice carrying universal Flp recombinase inverts the SA-βgeo-pA at heterotypic recognition targets (frt and F3 sites) and simultaneously excises cognate recognition sites, resulting in progeny carrying the NIPBLFlox/+ allele. Inversion allows normal splicing between the endogenous NIPBL splice sites (Exon 1 to Exon 2), thereby yielding a phenotypically wildtype allele. NIPBLFlox/+ mice are similar to wildtype littermates in size: Image is of 3-wk-old male littermates; scatter plot shows weights of 11-wk-old NIPBLFlox/+ mice (red, n = 18: 4 female; 14 male) compared to wildtype littermates (black, n = 19: 4 female; 15 male) from 5 litters. Expression of β-geo is not detected by X-gal staining in E10.5 NIPBLFlox/+ embryos. Histogram shows qRT-PCR analysis of relative NIPBL expression in brain tissue of E17.5 in NIPBLFlox/+ (n = 8) versus wildtype littermates (n = 7), plotted as in B; p > 0.05, Student’s t test. D. Mating NIPBLFLEX/+ mice with mice carrying a universal Cre recombinase causes recombination of the NIPBLFLEX allele (at LoxP and lox5171 recognition sites), resulting in progeny carrying the NIPBLFlrt allele. NIPBLFlrt/+mice are phenotypically wildtype: Image is of male NIPBLFlrt/+ and wildtype littermates at 3 wk of age showing no apparent difference in body size. Scatter plot shows weights of 12-wk-old NIPBLFlrt/+ mice (red, n = 19: 6 female; 13 male) and wildtype littermates (black, n = 10: 3 female; 7 male) from 3 litters. Expression of β-geo was not detected by X-gal staining in E10.5 NIPBLFlrt/+ embryos. qRT-PCR results show relative NIPBL expression in kidneys of E17.5 NIPBLFlrt/+ (n = 6) compared to wildtype littermates (n = 6), plotted as in B; p > 0.05 by Student’s t test. E. Cre-mediated recombination of mice carrying the NIPBLFlox allele, obtained by crossing NIPBLFlox/+ mice with Nanog-Cre hemizygous mice, results in re-inversion of the SA-βgeo-pA cassette and re-trapping of NIPBL expression. Resulting progeny (NIPBLFIN/+ mice) are phenotypically mutant, and survive poorly, with only 13 NIPBLFIN/+ mice (4%) surviving to weaning age out of 315 total pups born (significantly less than the expected 25% survival, p < 0.001 by Chi-square analysis). Adult NIPBLFIN/+ mice are smaller than wildtype littermates: Image is of 6-wk old males; scatter plot shows weights of 8-wk-old NIPBLFIN/+ mice (red, n = 11: 4 females; 7 males) compared to wildtype littermates (black, n = 7: 3 females; 4 males) from 16 litters. Ubiquitous expression of β-geo is detected by X-gal staining. qRT-PCR results show reduced NIPBL expression in brains of E17.5 NIPBLFIN/+ (n = 7) compared to wildtype littermates (n = 6), plotted as in B; asterisk: p < 0.05, Student’s t test. Scale bars = 1 mm for all panels. Frt (purple triangles), F3 (green triangles), loxP (orange triangles) and lox5171 (yellow triangles); SA, splice acceptor; β-geo, β-galactosidase/neomycin phosphotransferase fusion gene; pA, bovine growth hormone polyadenylation sequence.
Ebony Flowers - One of the best experts on this subject based on the ideXlab platform.
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the cohesin loader NIPBL interacts with pre ribosomal rna and treacle to regulate ribosomal rna synthesis
bioRxiv, 2019Co-Authors: Xiangduo Kong, Yenyun Chen, Ebony Flowers, Jianhuang Lin, Eric L Van Nostrand, Steven M Blue, Jonathan ChauAbstract:Abstract NIPBL is an essential loader of cohesin to mediate sister chromatid cohesion and chromatin loop organization. NIPBL mutations cause Cornelia de Lange Syndrome. How NIPBL’s genomic localization is specified is not fully understood. We found that NIPBL localizes to the nucleolus in an RNA-dependent manner and binds directly to ribosomal RNA (rRNA). We identified two RNA binding domains in NIPBL in vitro, both of which are required for efficient rRNA binding in vivo. NIPBL binds to ribosomal DNA (rDNA) in an RNA-stimulated manner, recruits PAF1 and promotes pre-rRNA transcription. Stress that inhibits rRNA synthesis displaces NIPBL from the nucleolus and rDNA. Interestingly, treacle, mutated in Treacher Collins syndrome, tightly binds to and recruits NIPBL to the nucleolus, nucleolar organizer regions, and the stress-induced nucleolar cap. The results reveal that a subpopulation of NIPBL is recruited to the nucleolus through its interaction with RNA and treacle and regulates pre-rRNA transcription.
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the effect of nipped b like NIPBL haploinsufficiency on genome wide cohesin binding and target gene expression modeling cornelia de lange syndrome
Clinical Epigenetics, 2017Co-Authors: Daniel A Newkirk, Yenyun Chen, Richard Chien, Weihua Zeng, Jacob Biesinger, Ebony Flowers, Shimako KawauchiAbstract:Background Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder frequently associated with heterozygous loss-of-function mutations of Nipped-B-like (NIPBL), the human homolog of Drosophila Nipped-B. NIPBL loads cohesin onto chromatin. Cohesin mediates sister chromatid cohesion important for mitosis but is also increasingly recognized as a regulator of gene expression. In CdLS patient cells and animal models, expression changes of multiple genes with little or no sister chromatid cohesion defect suggests that disruption of gene regulation underlies this disorder. However, the effect of NIPBL haploinsufficiency on cohesin binding, and how this relates to the clinical presentation of CdLS, has not been fully investigated. NIPBL haploinsufficiency causes CdLS-like phenotype in mice. We examined genome-wide cohesin binding and its relationship to gene expression using mouse embryonic fibroblasts (MEFs) from NIPBL+/− mice that recapitulate the CdLS phenotype.
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the effect of nipped b like NIPBL haploinsufficiency on genome wide cohesin binding and target gene expression modeling cornelia de lange syndrome
Clinical Epigenetics, 2017Co-Authors: Daniel A Newkirk, Yenyun Chen, Richard Chien, Weihua Zeng, Jacob Biesinger, Ebony Flowers, Shimako KawauchiAbstract:Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder frequently associated with heterozygous loss-of-function mutations of Nipped-B-like (NIPBL), the human homolog of Drosophila Nipped-B. NIPBL loads cohesin onto chromatin. Cohesin mediates sister chromatid cohesion important for mitosis but is also increasingly recognized as a regulator of gene expression. In CdLS patient cells and animal models, expression changes of multiple genes with little or no sister chromatid cohesion defect suggests that disruption of gene regulation underlies this disorder. However, the effect of NIPBL haploinsufficiency on cohesin binding, and how this relates to the clinical presentation of CdLS, has not been fully investigated. NIPBL haploinsufficiency causes CdLS-like phenotype in mice. We examined genome-wide cohesin binding and its relationship to gene expression using mouse embryonic fibroblasts (MEFs) from NIPBL+/− mice that recapitulate the CdLS phenotype. We found a global decrease in cohesin binding, including at CCCTC-binding factor (CTCF) binding sites and repeat regions. Cohesin-bound genes were found to be enriched for histone H3 lysine 4 trimethylation (H3K4me3) at their promoters; were disproportionately downregulated in NIPBL mutant MEFs; and displayed evidence of reduced promoter-enhancer interaction. The results suggest that gene activation is the primary cohesin function sensitive to NIPBL reduction. Over 50% of significantly dysregulated transcripts in mutant MEFs come from cohesin target genes, including genes involved in adipogenesis that have been implicated in contributing to the CdLS phenotype. Decreased cohesin binding at the gene regions is directly linked to disease-specific expression changes. Taken together, our NIPBL haploinsufficiency model allows us to analyze the dosage effect of cohesin loading on CdLS development.
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the effect of nipped b like NIPBL haploinsufficiency on genome wide cohesin binding and target gene expression modeling cornelia de lange syndrome
bioRxiv, 2017Co-Authors: Daniel A Newkirk, Anne L. Calof, Yenyun Chen, Richard Chien, Weihua Zeng, Jacob Biesinger, Ebony Flowers, Shimako Kawauchi, Rosaysela Santos, Arthur D. LanderAbstract:Cornelia de Lange Syndrome (CdLS) is a multisystem developmental disorder frequently associated with heterozygous loss-of-function mutations of Nipped-B-like (NIPBL), the human homolog of Drosophila Nipped-B. NIPBL loads cohesin onto chromatin. Cohesin mediates sister chromatid cohesion important for mitosis, but is also increasingly recognized as a regulator of gene expression. In CdLS patient cells and animal models, the presence of multiple gene expression changes with little or no sister chromatid cohesion defect suggests that disruption of gene regulation underlies this disorder. However, the effect of NIPBL haploinsufficiency on cohesin binding, and how this relates to the clinical presentation of CdLS, has not been fully investigated. NIPBL haploinsufficiency causes CdLS-like phenotype in mice. We examined genome-wide cohesin binding and its relationship to gene expression using mouse embryonic fibroblasts (MEFs) from NIPBL +/- mice that recapitulate the CdLS phenotype. We found a global decrease in cohesin binding, including at CCCTC-binding factor (CTCF) binding sites and repeat regions. Cohesin-bound genes were found to be enriched for histone H3 lysine 4 trimethylation (H3K4me3) at their promoters; were disproportionately downregulated in NIPBL mutant MEFs; and displayed evidence of reduced promoter-enhancer interaction. The results suggest that gene activation is the primary cohesin function sensitive to NIPBL reduction. Over 50% of significantly dysregulated transcripts in mutant MEFs come from cohesin target genes, including genes involved in adipogenesis that have been implicated in contributing to the CdLS phenotype. Thus, decreased cohesin binding at the gene regions directly contributes to disease-specific expression changes. Taken together, our NIPBL haploinsufficiency model allows us to analyze the dosage effect of cohesin loading on CdLS development.
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the role of NIPBL in cornelia de lange syndrome
2015Co-Authors: Daniel A Newkirk, Ebony Flowers, S Kawauchi, Rosaysela Santos, Y Y Chen, X Zeng, X Kong, C Yao, A Ball, A L CalofAbstract:Author(s): Newkirk, DA; Chen, YY; Flowers, E; Zeng, X; Kong, X; Yao, C; Ball, A; Kawauchi, S; Santos, R; Calof, AL; Lander, AD; Shi, Y; Xie, X; Yokomori, K | Abstract: Cornelia de Lange Syndrome (CdLS) is a severe developmental disorder frequently associated with heterozygous loss-of-function NIPBL mutations. NIPBL loads cohesin onto chromatin. Cohesin mediates sister chromatid cohesion important for mitosis, but is also increasingly being recognized as a regulator of gene expression. In CdLS patient cells and animal models, the presence of multiple gene expression changes with little or no cohesion defect suggests that disruption of gene regulation underlies this disorder. However, the effect of NIP BL haploinsufficiency on cohesin binding, and how this relates .to the clinical presentation of CdLS, has not been fully investigated. We examined genome-wide cohesin binding and its relationship to gene expression using mouse embryonic fibroblasts (MEFs) from NIPBL +I- mice that recapitulate the CdLS phenotype. We found a global decrease in cohesin binding, including those at CTCF sites and repeat regions. Cohesin-bound genes are enriched for H3K4me3 at the promoters and are mostly downregulated in NIPBL mutant MEFs with evidence for reduced promoter- enhancer interaction, suggesting that gene activation is the primary co he sin function sensitive to Nip bl reduction. Over 50% of genes affected in mutant MEFs are cohesin target genes, including those involved in adipogenesis, indicating their direct contributions to the NIPBL haploinsufficiency-induced CdLS phenotype. Interestingly, mutations in several cohesin subunit genes exhibit mild and somewhat distinct phenotypes compared to that of NIP BL haploinsufficiency, raising the possibility that NIPBL may have unique functions independent of cohesin. We will discuss our recent findings that su11port the notion that the cohesin-independent role ofNIPBL also contributes to the CdLS pathogenesis. This work was supported in part by NIH grants P01-HD052860 and R21 HD062951.
Arthur D. Lander - One of the best experts on this subject based on the ideXlab platform.
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the effect of nipped b like NIPBL haploinsufficiency on genome wide cohesin binding and target gene expression modeling cornelia de lange syndrome
bioRxiv, 2017Co-Authors: Daniel A Newkirk, Anne L. Calof, Yenyun Chen, Richard Chien, Weihua Zeng, Jacob Biesinger, Ebony Flowers, Shimako Kawauchi, Rosaysela Santos, Arthur D. LanderAbstract:Cornelia de Lange Syndrome (CdLS) is a multisystem developmental disorder frequently associated with heterozygous loss-of-function mutations of Nipped-B-like (NIPBL), the human homolog of Drosophila Nipped-B. NIPBL loads cohesin onto chromatin. Cohesin mediates sister chromatid cohesion important for mitosis, but is also increasingly recognized as a regulator of gene expression. In CdLS patient cells and animal models, the presence of multiple gene expression changes with little or no sister chromatid cohesion defect suggests that disruption of gene regulation underlies this disorder. However, the effect of NIPBL haploinsufficiency on cohesin binding, and how this relates to the clinical presentation of CdLS, has not been fully investigated. NIPBL haploinsufficiency causes CdLS-like phenotype in mice. We examined genome-wide cohesin binding and its relationship to gene expression using mouse embryonic fibroblasts (MEFs) from NIPBL +/- mice that recapitulate the CdLS phenotype. We found a global decrease in cohesin binding, including at CCCTC-binding factor (CTCF) binding sites and repeat regions. Cohesin-bound genes were found to be enriched for histone H3 lysine 4 trimethylation (H3K4me3) at their promoters; were disproportionately downregulated in NIPBL mutant MEFs; and displayed evidence of reduced promoter-enhancer interaction. The results suggest that gene activation is the primary cohesin function sensitive to NIPBL reduction. Over 50% of significantly dysregulated transcripts in mutant MEFs come from cohesin target genes, including genes involved in adipogenesis that have been implicated in contributing to the CdLS phenotype. Thus, decreased cohesin binding at the gene regions directly contributes to disease-specific expression changes. Taken together, our NIPBL haploinsufficiency model allows us to analyze the dosage effect of cohesin loading on CdLS development.
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Haploinsufficiency for Nkx2-5 increases the incidence and severity of heart defects in NIPBL-deficient embryos.
2016Co-Authors: Rosaysela Santos, Martha E. Lopez-burks, Shimako Kawauchi, Russell E. Jacobs, Hojae Choi, Jamie Wikenheiser, Benedikt Hallgrimsson, Heather A. Jamniczky, Scott E. Fraser, Arthur D. LanderAbstract:A. NIPBL+/-;Nkx2-5+/- mice displayed ASDs (yellow arrowhead), VSDs (green arrowhead), and/or PTAs (black asterisk). B. Histogram showing increases in frequency and types of heart defects in NIPBL+/-;Nkx2-5+/- hearts compared to littermates of various genotypes; number of hearts observed with each type of defect is indicated. Data show that the overall incidence of defects in NIPBL+/-;Nkx2-5+/- hearts (83%) is significantly greater than in either NIPBL+/- (30%, p = 0.011 by Chi square) or Nkx2.5+/- (13%, p = 0.001 by Chi-square) hearts. C. Gross overview of the great vessels highlighting PTA in NIPBL+/-;Nkx2-5+/- mice. D. Heart position and morphology in a subset of NIPBL+/-;Nkx2-5+/- mice was drastically different than in littermates. Arrows indicate the position of the trachea (Tr), dotted lines originate at the pulmonary artery and ends at the apex of the heart; note drastic change in the angle of dotted line in NIPBL+/-;Nkx2-5+/- heart. E. Ventricular volumes for hearts of each genotype; horizontal bars indicate means. Ventricular volumes of NIPBL+/-;Nkx2-5+/- hearts (n = 6) were similar in size to NIPBL+/- hearts (n = 5) (Mann-Whitney U, p > 0.05), whereas control hearts (wildtype n = 5 and Nkx2-5+/-, n = 5) were significantly larger than the hearts of their NIPBL+/- and NIPBL+/-;Nkx2-5+/- littermates (red asterisks: Mann-Whitney U, p < 0.05). ao, aorta; ASD, atrial septal defect; la, left atrium; lv, left ventricle; pa, pulmonary artery; PTA, persistent truncus arteriosus; ra, right atrium; rv, right ventricle; Tr, trachea; VSD, ventricular septal defect; Size bar = 500 μm.
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FLEX alleles allow successive toggling between mutant and wildtype genotypes and phenotypes.
2016Co-Authors: Rosaysela Santos, Martha E. Lopez-burks, Shimako Kawauchi, Russell E. Jacobs, Hojae Choi, Jamie Wikenheiser, Benedikt Hallgrimsson, Heather A. Jamniczky, Scott E. Fraser, Arthur D. LanderAbstract:A. Schematic of EUCE313f02 (NIPBLFLEX) allele from which the NIPBLFLEX/+ mouse line and allelic series are derived. The rsFlp-Rosa-βgeo cassette is inserted 14.5 kbp downstream of NIPBL Exon 1 on Chromosome 15. B. In the NIPBLFLEX allele, the splice acceptor (SA) in the cassette traps NIPBL expression, resulting in termination of NIPBL expression after exon 1 and expression of the β-geo reporter for the trapped null allele. Adult NIPBLFLEX/+ mice are smaller than wildtype littermates: Image is of 4-wk-old male littermates. Scatter plot shows weights of 12-wk-old NIPBLFLEX/+ mice (red, n = 3: 1 female, 2 males) and wildtype littermates (black, n = 8: 4 females, 4 males) from 3 litters. Ubiquitous expression of β-geo was detected by X-gal staining in E10.5 NIPBLFLEX/+ embryos. Histogram shows mean ± SEM of relative NIPBL expression, assessed by qRT-PCR, in kidneys of E17.5 NIPBLFLEX/+ (n = 8) and wildtype littermates (n = 6); asterisk: p < 0.05 by Student’s t test. C. Mating NIPBLFLEX/+ mice with mice carrying universal Flp recombinase inverts the SA-βgeo-pA at heterotypic recognition targets (frt and F3 sites) and simultaneously excises cognate recognition sites, resulting in progeny carrying the NIPBLFlox/+ allele. Inversion allows normal splicing between the endogenous NIPBL splice sites (Exon 1 to Exon 2), thereby yielding a phenotypically wildtype allele. NIPBLFlox/+ mice are similar to wildtype littermates in size: Image is of 3-wk-old male littermates; scatter plot shows weights of 11-wk-old NIPBLFlox/+ mice (red, n = 18: 4 female; 14 male) compared to wildtype littermates (black, n = 19: 4 female; 15 male) from 5 litters. Expression of β-geo is not detected by X-gal staining in E10.5 NIPBLFlox/+ embryos. Histogram shows qRT-PCR analysis of relative NIPBL expression in brain tissue of E17.5 in NIPBLFlox/+ (n = 8) versus wildtype littermates (n = 7), plotted as in B; p > 0.05, Student’s t test. D. Mating NIPBLFLEX/+ mice with mice carrying a universal Cre recombinase causes recombination of the NIPBLFLEX allele (at LoxP and lox5171 recognition sites), resulting in progeny carrying the NIPBLFlrt allele. NIPBLFlrt/+mice are phenotypically wildtype: Image is of male NIPBLFlrt/+ and wildtype littermates at 3 wk of age showing no apparent difference in body size. Scatter plot shows weights of 12-wk-old NIPBLFlrt/+ mice (red, n = 19: 6 female; 13 male) and wildtype littermates (black, n = 10: 3 female; 7 male) from 3 litters. Expression of β-geo was not detected by X-gal staining in E10.5 NIPBLFlrt/+ embryos. qRT-PCR results show relative NIPBL expression in kidneys of E17.5 NIPBLFlrt/+ (n = 6) compared to wildtype littermates (n = 6), plotted as in B; p > 0.05 by Student’s t test. E. Cre-mediated recombination of mice carrying the NIPBLFlox allele, obtained by crossing NIPBLFlox/+ mice with Nanog-Cre hemizygous mice, results in re-inversion of the SA-βgeo-pA cassette and re-trapping of NIPBL expression. Resulting progeny (NIPBLFIN/+ mice) are phenotypically mutant, and survive poorly, with only 13 NIPBLFIN/+ mice (4%) surviving to weaning age out of 315 total pups born (significantly less than the expected 25% survival, p < 0.001 by Chi-square analysis). Adult NIPBLFIN/+ mice are smaller than wildtype littermates: Image is of 6-wk old males; scatter plot shows weights of 8-wk-old NIPBLFIN/+ mice (red, n = 11: 4 females; 7 males) compared to wildtype littermates (black, n = 7: 3 females; 4 males) from 16 litters. Ubiquitous expression of β-geo is detected by X-gal staining. qRT-PCR results show reduced NIPBL expression in brains of E17.5 NIPBLFIN/+ (n = 7) compared to wildtype littermates (n = 6), plotted as in B; asterisk: p < 0.05, Student’s t test. Scale bars = 1 mm for all panels. Frt (purple triangles), F3 (green triangles), loxP (orange triangles) and lox5171 (yellow triangles); SA, splice acceptor; β-geo, β-galactosidase/neomycin phosphotransferase fusion gene; pA, bovine growth hormone polyadenylation sequence.
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NIPBL and mediator cooperatively regulate gene expression to control limb development.
PLOS Genetics, 2014Co-Authors: Akihiko Muto, Martha E. Lopez-burks, Yutaka Kikuchi, Anne L. Calof, Arthur D. Lander, Shingo Ikeda, Thomas F. SchillingAbstract:Haploinsufficiency for NIPBL, a cohesin loading protein, causes Cornelia de Lange Syndrome (CdLS), the most common “cohesinopathy”. It has been proposed that the effects of NIPBL-haploinsufficiency result from disruption of long-range communication between DNA elements. Here we use zebrafish and mouse models of CdLS to examine how transcriptional changes caused by NIPBL deficiency give rise to limb defects, a common condition in individuals with CdLS. In the zebrafish pectoral fin (forelimb), knockdown of NIPBL expression led to size reductions and patterning defects that were preceded by dysregulated expression of key early limb development genes, including fgfs, shha, hand2 and multiple hox genes. In limb buds of NIPBL-haploinsufficient mice, transcriptome analysis revealed many similar gene expression changes, as well as altered expression of additional classes of genes that play roles in limb development. In both species, the pattern of dysregulation of hox-gene expression depended on genomic location within the Hox clusters. In view of studies suggesting that NIPBL colocalizes with the mediator complex, which facilitates enhancer-promoter communication, we also examined zebrafish deficient for the Med12 Mediator subunit, and found they resembled NIPBL-deficient fish in both morphology and gene expression. Moreover, combined partial reduction of both NIPBL and Med12 had a strongly synergistic effect, consistent with both molecules acting in a common pathway. In addition, three-dimensional fluorescent in situ hybridization revealed that NIPBL and Med12 are required to bring regions containing long-range enhancers into close proximity with the zebrafish hoxda cluster. These data demonstrate a crucial role for NIPBL in limb development, and support the view that its actions on multiple gene pathways result from its influence, together with Mediator, on regulation of long-range chromosomal interactions.
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localisation of the smc loading complex NIPBL mau2 during mammalian meiotic prophase i
Chromosoma, 2014Co-Authors: Torkild Visnes, Anne L. Calof, Arthur D. Lander, Fosco Giordano, A Kuznetsova, Jose A Suja, Lena StromAbstract:Evidence from lower eukaryotes suggests that the chromosomal associations of all the structural maintenance of chromosome (SMC) complexes, cohesin, condensin and Smc5/6, are influenced by the NIPBL/Mau2 heterodimer. Whether this function is conserved in mammals is currently not known. During mammalian meiosis, very different localisation patterns have been reported for the SMC complexes, and the localisation of NIPBL/Mau2 has just recently started to be investigated. Here, we show that NIPBL/Mau2 binds on chromosomal axes from zygotene to mid-pachytene in germ cells of both sexes. In spermatocytes, NIPBL/Mau2 then relocalises to chromocenters, whereas in oocytes it remains bound to chromosomal axes throughout prophase to dictyate arrest. The localisation pattern of NIPBL/Mau2, together with those seen for cohesin, condensin and Smc5/6 subunits, is consistent with a role as a loading factor for cohesin and condensin I, but not for Smc5/6. We also demonstrate that NIPBL/Mau2 localises next to Rad51 and γH2AX foci. NIPBL gene deficiencies are associated with the Cornelia de Lange syndrome in humans, and we find that haploinsufficiency of the orthologous mouse gene results in an altered distribution of double-strand breaks marked by γH2AX during prophase I. However, this is insufficient to result in major meiotic malfunctions, and the chromosomal associations of the synaptonemal complex proteins and the three SMC complexes appear cytologically indistinguishable in wild-type and NIPBL +/− spermatocytes.
Anne L. Calof - One of the best experts on this subject based on the ideXlab platform.
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the effect of nipped b like NIPBL haploinsufficiency on genome wide cohesin binding and target gene expression modeling cornelia de lange syndrome
bioRxiv, 2017Co-Authors: Daniel A Newkirk, Anne L. Calof, Yenyun Chen, Richard Chien, Weihua Zeng, Jacob Biesinger, Ebony Flowers, Shimako Kawauchi, Rosaysela Santos, Arthur D. LanderAbstract:Cornelia de Lange Syndrome (CdLS) is a multisystem developmental disorder frequently associated with heterozygous loss-of-function mutations of Nipped-B-like (NIPBL), the human homolog of Drosophila Nipped-B. NIPBL loads cohesin onto chromatin. Cohesin mediates sister chromatid cohesion important for mitosis, but is also increasingly recognized as a regulator of gene expression. In CdLS patient cells and animal models, the presence of multiple gene expression changes with little or no sister chromatid cohesion defect suggests that disruption of gene regulation underlies this disorder. However, the effect of NIPBL haploinsufficiency on cohesin binding, and how this relates to the clinical presentation of CdLS, has not been fully investigated. NIPBL haploinsufficiency causes CdLS-like phenotype in mice. We examined genome-wide cohesin binding and its relationship to gene expression using mouse embryonic fibroblasts (MEFs) from NIPBL +/- mice that recapitulate the CdLS phenotype. We found a global decrease in cohesin binding, including at CCCTC-binding factor (CTCF) binding sites and repeat regions. Cohesin-bound genes were found to be enriched for histone H3 lysine 4 trimethylation (H3K4me3) at their promoters; were disproportionately downregulated in NIPBL mutant MEFs; and displayed evidence of reduced promoter-enhancer interaction. The results suggest that gene activation is the primary cohesin function sensitive to NIPBL reduction. Over 50% of significantly dysregulated transcripts in mutant MEFs come from cohesin target genes, including genes involved in adipogenesis that have been implicated in contributing to the CdLS phenotype. Thus, decreased cohesin binding at the gene regions directly contributes to disease-specific expression changes. Taken together, our NIPBL haploinsufficiency model allows us to analyze the dosage effect of cohesin loading on CdLS development.
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Abnormalities of Limb Development in Vertebrate Animal Models of CdLS
eScholarship University of California, 2015Co-Authors: Anne L. Calof, Martha E. Lopez-burks, Muto A, Schilling T, A D LanderAbstract:Recent studies implicate the cohesin complex in transcriptional control, potentially through influences on long-distance communication between DNA elements. Animal models of Cornelia de Lange Syndrome (CdLS), the most common “cohesinopathy,” provide a unique opportunity to investigate both how cohesin regulates transcription, and the physiological consequences of disrupting that action. CdLS is most commonly caused by haploinsufficiency for NIPBL, a protein important for loading cohesin onto chromosomes, and individuals with CdLS frequently exhibit limb defects, particularly forelimb reductions of varying severity. Although NIPBL-deficient mice (NIPBL þ/ mice), display no gross limb abnormalities, we find that NIPBL-deficient zebrafish exhibit severe reduction defects of the pectoral fins, the homologues of the mammalian forelimb. These defects are preceded by dysregulated expression of key developmental genes in the early limb (fin) bud, including fgfs in the apical ectodermal ridge; and shha, hand2, and hox genes in limb mesenchyme. Intriguingly, a strikingly similar pattern of gene expression changes can be detected in the limb buds of NIPBL-haploinsufficient mice, although the magnitude of gene expression changes is smaller. Limb bud-specific expression of Shh and Hox genes is known to be controlled by long-range enhancerpromoter interactions, and the pattern of changes in hox expression that occurs in NIPBL-deficient fin buds—characterized by downregulation of 5 0 hox genes and up-regulation of 3 0 hox genes—is consistent with the impairment of such long-range effects. Interestingly, knocking down expression of Med12—a subunit of the Mediator complex, which regulates promoter-enhancer communication and can co-localize with NIPBL on DNA—phenocopies morphological and transcriptional changes observed in NIPBLdeficient fin buds. Moreover, partial reductions of NIPBL and Med12 interact synergistically, suggesting action in a common pathway. Overall, the data support the view that NIPBL and cohesin, most likely acting in concert with the Mediator complex, regulate limb-specific gene expression and limb development by influencing long-range chromosomal interactions, and suggest that these changes in expression in NIPBL-deficient limbs and fins are pathophysiologically significant in CdLS. Supported by NIH grant P01- HD052860 to ALC and ADL
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NIPBL and mediator cooperatively regulate gene expression to control limb development.
PLOS Genetics, 2014Co-Authors: Akihiko Muto, Martha E. Lopez-burks, Yutaka Kikuchi, Anne L. Calof, Arthur D. Lander, Shingo Ikeda, Thomas F. SchillingAbstract:Haploinsufficiency for NIPBL, a cohesin loading protein, causes Cornelia de Lange Syndrome (CdLS), the most common “cohesinopathy”. It has been proposed that the effects of NIPBL-haploinsufficiency result from disruption of long-range communication between DNA elements. Here we use zebrafish and mouse models of CdLS to examine how transcriptional changes caused by NIPBL deficiency give rise to limb defects, a common condition in individuals with CdLS. In the zebrafish pectoral fin (forelimb), knockdown of NIPBL expression led to size reductions and patterning defects that were preceded by dysregulated expression of key early limb development genes, including fgfs, shha, hand2 and multiple hox genes. In limb buds of NIPBL-haploinsufficient mice, transcriptome analysis revealed many similar gene expression changes, as well as altered expression of additional classes of genes that play roles in limb development. In both species, the pattern of dysregulation of hox-gene expression depended on genomic location within the Hox clusters. In view of studies suggesting that NIPBL colocalizes with the mediator complex, which facilitates enhancer-promoter communication, we also examined zebrafish deficient for the Med12 Mediator subunit, and found they resembled NIPBL-deficient fish in both morphology and gene expression. Moreover, combined partial reduction of both NIPBL and Med12 had a strongly synergistic effect, consistent with both molecules acting in a common pathway. In addition, three-dimensional fluorescent in situ hybridization revealed that NIPBL and Med12 are required to bring regions containing long-range enhancers into close proximity with the zebrafish hoxda cluster. These data demonstrate a crucial role for NIPBL in limb development, and support the view that its actions on multiple gene pathways result from its influence, together with Mediator, on regulation of long-range chromosomal interactions.
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localisation of the smc loading complex NIPBL mau2 during mammalian meiotic prophase i
Chromosoma, 2014Co-Authors: Torkild Visnes, Anne L. Calof, Arthur D. Lander, Fosco Giordano, A Kuznetsova, Jose A Suja, Lena StromAbstract:Evidence from lower eukaryotes suggests that the chromosomal associations of all the structural maintenance of chromosome (SMC) complexes, cohesin, condensin and Smc5/6, are influenced by the NIPBL/Mau2 heterodimer. Whether this function is conserved in mammals is currently not known. During mammalian meiosis, very different localisation patterns have been reported for the SMC complexes, and the localisation of NIPBL/Mau2 has just recently started to be investigated. Here, we show that NIPBL/Mau2 binds on chromosomal axes from zygotene to mid-pachytene in germ cells of both sexes. In spermatocytes, NIPBL/Mau2 then relocalises to chromocenters, whereas in oocytes it remains bound to chromosomal axes throughout prophase to dictyate arrest. The localisation pattern of NIPBL/Mau2, together with those seen for cohesin, condensin and Smc5/6 subunits, is consistent with a role as a loading factor for cohesin and condensin I, but not for Smc5/6. We also demonstrate that NIPBL/Mau2 localises next to Rad51 and γH2AX foci. NIPBL gene deficiencies are associated with the Cornelia de Lange syndrome in humans, and we find that haploinsufficiency of the orthologous mouse gene results in an altered distribution of double-strand breaks marked by γH2AX during prophase I. However, this is insufficient to result in major meiotic malfunctions, and the chromosomal associations of the synaptonemal complex proteins and the three SMC complexes appear cytologically indistinguishable in wild-type and NIPBL +/− spermatocytes.
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reduction of NIPBL impairs cohesin loading locally and affects transcription but not cohesion dependent functions in a mouse model of cornelia de lange syndrome
Biochimica et Biophysica Acta, 2013Co-Authors: Silvia Remeseiro, Anne L. Calof, Arthur D. Lander, Shimako Kawauchi, Ana Cuadrado, Ana LosadaAbstract:Cornelia de Lange Syndrome (CdLS) is a genetic disorder linked to mutations in cohesin and its regulators. To date, it is unclear which function of cohesin is more relevant to the pathology of the syndrome. A mouse heterozygous for the gene encoding the cohesin loader NIPBL recapitulates many features of CdLS. We have carefully examined NIPBL deficient cells and here report that they have robust cohesion all along the chromosome. DNA replication, DNA repair and chromosome segregation are carried out efficiently in these cells. While bulk cohesin loading is unperturbed, binding to certain promoters such as the Protocadherin genes in brain is notably affected and alters gene expression. These results provide further support for the idea that developmental defects in CdLS are caused by deregulated transcription and not by malfunction of cohesion-related processes.
Ian D Krantz - One of the best experts on this subject based on the ideXlab platform.
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NIPBL expression levels in cdls probands as a predictor of mutation type and phenotypic severity
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2016Co-Authors: Maninder Kaur, Matthew A Deardorff, Devanshi Mehta, Sarah E Noon, Zhe Zhang, Ian D KrantzAbstract:Cornelia de Lange syndrome (CdLS) is a rare, genetically heterogeneous multisystem developmental disorder with a high degree of variability in its clinical presentation. Approximately 65% of probands harbor mutations in genes that encode core components (SMC1A, SMC3, and RAD21) or regulators (NIPBL, HDAC8) of the cohesin complex, of which mutations in NIPBL are the most common. Cohesin plays a canonical role in sister chromatid cohesion during cell division and non-canonical roles in DNA repair, stem cell maintenance and differentiation, and regulation of gene expression. Disruption of the latter role seems to be the major contributor to the underlying molecular pathogenesis of CdLS. NIPBL is required for loading and unloading the cohesin complex onto chromosomes. The expression levels of NIPBL itself appear to be tightly regulated and highly evolutionarily conserved. Droplet digital PCR was used to quantify NIPBL mRNA expression levels with high precision from a cohort of 37 samples (NIPBL, SMC1A, SMC3, and HDAC8 mutation positive probands and negative control). Probands with severe forms of CdLS or severe mutation types were found to have lower levels of NIPBL in comparison to phenotypically milder patients and controls. Levels of NIPBL also correlated with the presence of mutations in different CdLS-causing genes. The data suggests that NIPBL levels are closely correlated with the severity of CdLS and with specific causative genes and types of mutations. ddPCR may provide a tool to assist in diagnostic approaches to CdLS, for genetic counseling and prognosis, and for monitoring potential therapeutic modalities in the future. © 2016 Wiley Periodicals, Inc.
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cornelia de lange syndrome
Jcpsp-journal of The College of Physicians and Surgeons Pakistan, 2016Co-Authors: Matthew A Deardorff, Sarah E Noon, Ian D KrantzAbstract:Clinical characteristics Classic Cornelia de Lange syndrome (CdLS) is characterized by distinctive facial features, growth retardation (prenatal onset; Diagnosis/testing Diagnosis is based on clinical findings and/or the identification of a heterozygous pathogenic variant in NIPBL, RAD21, or SMC3 or a hemizygous pathogenic variant in HDAC8 or SMC1A. Management Treatment of manifestations: Aggressive management of gastroesophageal reflux with assessment of potential gastrointestinal malrotation in all affected individuals; consideration of fundoplication if reflux is severe. Supplementary formulas and/or gastrostomy tube placement to meet nutritional needs as necessary. Physical, occupational, and speech therapy to optimize psychomotor development and communication skills. Standard treatment for hearing loss, cardiac defects, seizures, vesicoureteral reflux, and cryptorchidism. Prevention of secondary complications: Preoperative evaluation for thrombocytopenia and cardiac disease with careful monitoring of the airway during anesthesia; malignant hyperthermia precautions. Surveillance: Annual GI evaluation, monitoring of growth and psychomotor development; routine eye and hearing evaluations, and monitoring of heart and kidney abnormalities. Genetic counseling NIPBL-related CdLS, RAD21-related CdLS, and SMC3-related CdLS are inherited in an autosomal dominant manner; HDAC8-related CdLS and SMC1A-related CdLS are inherited in an X-linked manner. The majority of affected individuals have a de novo heterozygous pathogenic variant in NIPBL; fewer than 1% of individuals with NIPBL-related CdLS have an affected parent. When the parents are clinically unaffected, the risk to the sibs of a proband with NIPBL-related CdLS is estimated to be 1.5% because of the possibility of germline mosaicism. The risk to sibs of a proband with HDAC8-related CdLS or SMC1A-related CdLS depends on the status of the proband's mother. Prenatal testing for pregnancies at increased risk is possible for families in which the pathogenic variant has been identified.
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NIPBL Controls RNA Biogenesis to Prevent Activation of the Stress Kinase PKR
Cell reports, 2015Co-Authors: Kobe C. Yuen, Ian D Krantz, Jennifer L. GertonAbstract:NIPBL, a cohesin loader, has been implicated in transcriptional control and genome organization. Mutations in NIPBL, cohesin, and its deacetylase HDAC8 result in Cornelia de Lange syndrome. We report activation of the RNA-sensing kinase PKR in human lymphoblastoid cell lines carrying NIPBL or HDAC8 mutations, but not SMC1A or SMC3 mutations. PKR activation can be triggered by unmodified RNAs. Gene expression profiles in NIPBL-deficient lymphoblastoid cells and mouse embryonic stem cells reveal lower expression of genes involved in RNA processing and modification. NIPBL mutant lymphoblastoid cells show reduced proliferation and protein synthesis with increased apoptosis, all of which are partially reversed by a PKR inhibitor. Non-coding RNAs from an NIPBL mutant line had less m(6)A modification and activated PKR activity in vitro. This study provides insight into the molecular pathology of Cornelia de Lange syndrome by establishing a relationship between NIPBL and HDAC8 mutations and PKR activation.
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a cohesin independent role for NIPBL at promoters provides insights in cdls
PLOS Genetics, 2014Co-Authors: Jessica Zuin, Ian D Krantz, Vedran Franke, Wilfred F J Van Ijcken, Antoine Van Der Sloot, Michael Van Der Reijden, Ryuichiro Nakato, Boris Lenhard, Kerstin S WendtAbstract:The cohesin complex is crucial for chromosome segregation during mitosis and has recently also been implicated in transcriptional regulation and chromatin architecture. The NIPBL protein is required for the loading of cohesin onto chromatin, but how and where cohesin is loaded in vertebrate cells is unclear. Heterozygous mutations of NIPBL were found in 50% of the cases of Cornelia de Lange Syndrome (CdLS), a human developmental syndrome with a complex phenotype. However, no defects in the mitotic function of cohesin have been observed so far and the links between NIPBL mutations and the observed developmental defects are unclear. We show that NIPBL binds to chromatin in somatic cells with a different timing than cohesin. Further, we observe that high-affinity NIPBL binding sites localize to different regions than cohesin and almost exclusively to the promoters of active genes. NIPBL or cohesin knockdown reduce transcription of these genes differently, suggesting a cohesin-independent role of NIPBL for transcription. Motif analysis and comparison to published data show that NIPBL co-localizes with a specific set of other transcription factors. In cells derived from CdLS patients NIPBL binding levels are reduced and several of the NIPBL-bound genes have previously been observed to be mis-expressed in CdLS. In summary, our observations indicate that NIPBL mutations might cause developmental defects in different ways. First, defects of NIPBL might lead to cohesin-loading defects and thereby alter gene expression and second, NIPBL deficiency might affect genes directly via its role at the respective promoters.
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NIPBL rearrangements in cornelia de lange syndrome evidence for replicative mechanism and genotype phenotype correlation
Genetics in Medicine, 2012Co-Authors: Davut Pehlivan, Ian D Krantz, Laird G Jackson, Melanie Hullings, Claudia M B Carvalho, Claudia Gonzagajauregui, Matthew A Deardorff, James R LupskiAbstract:NIPBL rearrangements in Cornelia de Lange syndrome: evidence for replicative mechanism and genotype–phenotype correlation