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Gene expression changes in limb buds of Nipbl-haploinsufficient mice

ABSTRACT: Multiple genes are dysregulated in hindlimb buds of Nipbl-deficient embryos. In all, more than 1000 limb bud genes were found to be significantly altered in expression by microarray analysis of E10.5 mouse hindlimb buds. Small changes in expression (mostly decreases) were observed for genes involved in FGF, BMP, and SHH pathways, as well as numerous genes involved in the Wnt/planar cell polarity signaling pathway. Genes involved in the Mediator complex, Cohesin function, and Hox gene expression and functions were also dysregulated in Nipbl deficient limb buds.

ORGANISM(S): Mus musculus

PROVIDER: GSE60932 | GEO | 2014/08/30

SECONDARY ACCESSION(S): PRJNA259854

REPOSITORIES: GEO

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Gene expression changes in limb buds of Nipbl-haploinsufficient mice

Project description:Multiple genes are dysregulated in hindlimb buds of Nipbl-deficient embryos. In all, more than 1000 limb bud genes were found to be significantly altered in expression by microarray analysis of E10.5 mouse hindlimb buds. Small changes in expression (mostly decreases) were observed for genes involved in FGF, BMP, and SHH pathways, as well as numerous genes involved in the Wnt/planar cell polarity signaling pathway. Genes involved in the Mediator complex, Cohesin function, and Hox gene expression and functions were also dysregulated in Nipbl deficient limb buds. Microarray analysis using RNA extracted from E10.5 hindlimb limb buds harvested from stage-matched Nipbl+/- (n=12) and wildtype (n=12)

2014-08-30 | E-GEOD-60932 | biostudies-arrayexpress

Transcriptome analysis of mouse embryonic fibroblasts of NIPBL-haploinsufficient mice

Project description:Cohesinopathies are characterized by mutations in the cohesin complex. Mutations in NIPBL, a cohesin loader, result in Cornelia de Lange syndrome (CdLS). CdLS is a congenital genetic disorder distinguished by craniofacial dysmorphism, abnormal upper limb development, delayed growth, severe cognitive retardation, and multiple organ malformations.It has been suggested that CdLS is caused by defects in the cohesin network that alter gene expression and genome organization. However, the precise molecular etiology of CdLS is largely unclear. To gain insights, we sequenced mRNAs isolated from mouse embryonic fibroblasts of both WT and NIPBL-haploinsufficient mice and compared their transcriptomes.

2015-10-01 | GSE64706 | GEO

Disruption of Nipbl/Scc2 in Cornelia de Lange Syndrome provokes cohesin genome-wide redistribution with an impact in the transcriptome

Project description:Cornelia de Lange syndrome (CdLS) is a rare disease affecting multiple organs and systems during development. Mutations in the cohesin loader, Nipbl/Scc2 were first described and are the most frequent in clinically diagnosed CdLS patients. The molecular mechanism driving the CdLS phenotypes are not understood. Apart from its canonical role in sister chromatid cohesion, cohesin has also been involved in the regulation of the spatial organization of the genome. Here, we investigated the transcriptome of CdLS-derived primary fibroblasts (gene expression microarray data included in the manuscript as an excel file) and observed the downregulation of genes involved in development and system skeletal organization providing a link to the developmental alterations and limb abnormalities characteristics of the CdLS patients. Genome-wide distribution studies demonstrated a global reduction of Nipbl at the Nipbl-associated high GC content regions in CdLS-derived cells. In addition, cohesin accumulates at Nipbl-occupied sites at CpG islands probably due to reduced cohesin translocation along chromosomes and fewer cohesin peaks colocalize with CTCF.

2021-05-27 | GSE145966 | GEO

Transcription profiling of mouse developing hindlimb bud to identify genes controlled by LMX1B

Project description:A control vs. genetic knockout experiment aimed at determining what RNAs are upregulated or downregulated in e11.5 mouse proximal limb tissue lacking the Lmx1b gene. Because Lmx1b is required for dorsal-ventral patterning of the limb, this screen gives insight into what putative downstream targets of Lmx1b contribute to dorsal-ventral patterning. Experiment Overall Design: The proximal portion of e11.5 hindlimb buds (~500um) was used for RNA extraction. Each array was hybridized with pooled cRNAs from both hindlimb buds of three embryos (6 hindlimbs/sample).

2008-04-08 | E-GEOD-10516 | biostudies-arrayexpress

Pitx1 broadly associates with limb enhancers and is enriched on hindlimb cis-regulatory elements

Project description:Extensive functional analyses have demonstrated that the pituitary homeodomain transcription factor Pitx1 plays a critical role in specifying hindlimb morphology in vertebrates. However, much less is known regarding the target genes and cis-regulatory elements through which Pitx1 acts. Earlier studies suggested that the hindlimb transcription factors Tbx4, HoxC10, and HoxC11 might be transcriptional targets of Pitx1, but definitive evidence for direct regulatory interactions has been lacking. Using ChIP-Seq on embryonic mouse hindlimbs, we have pinpointed the genome-wide location of Pitx1 binding sites during mouse hindlimb development and identified potential gene targets for Pitx1. We determined that Pitx1 binding is significantly enriched near genes involved in limb morphogenesis, including Tbx4, HoxC10, and HoxC11. Notably, Pitx1 is bound to the previously identified HLEA and HLEB hindlimb enhancers of the Tbx4 gene and to a newly identified Tbx2 hindlimb enhancer. Moreover, Pitx1 binding is significantly enriched on hindlimb relative to forelimb-specific cis-regulatory features that are differentially marked by H3K27ac. However, our analysis revealed that Pitx1 also strongly associates with many functionally verified limb enhancers that exhibit similar levels of activity in the embryonic mesenchyme of forelimbs and hindlimbs. We speculate that Pitx1 influences hindlimb morphology both through the activation of hindlimb specific enhancers as well as through the hindlimb-specific modulation of enhancers that are active in both sets of limbs. Embryonic hindlimb buds from 4 ICR mouse samples were used.

2012-12-01 | E-GEOD-41591 | biostudies-arrayexpress

Geminin is required for Hox gene regulation to pattern the developing limb

Project description:Development of the complex structure of the vertebrate limb requires carefully orchestrated interactions between multiple regulatory pathways and proteins. Among these, precise regulation of 5’ Hox transcription factor expression is essential for proper limb bud patterning and development. Here, we identified Geminin (Gmnn) as a novel regulator of this process. A conditional model of Gmnn deficiency resulted in loss or severe reduction of forelimb skeletal elements, while both the forelimb autopod and hindlimb were unaffected. 5’ Hox gene expression expanded into more proximal and anterior regions of embryonic forelimb buds in this Gmnn-deficient model. A second conditional model of Gmnn deficiency instead caused a similar but less severe reduction of hindlimb skeletal elements and hindlimb polydactyly, while not affecting the forelimb. An ectopic posterior Shh signaling center was evident in the anterior hindlimb bud of Gmnn-deficient embryos in this model. This center ectopically expressed Hoxd13, the Hoxd13 target Shh, and the Shh target Ptch1, while these mutant hindlimb buds also had reduced levels of the cleaved, repressor form of Gli3, a Shh pathway antagonist. Together, this work delineates a new role for Gmnn in modulating Hox expression to pattern the vertebrate limb.

2020-06-05 | GSE143211 | GEO

Mus musculus

Project description:Gene expression changes in limb buds of Nipbl-haploinsufficient mice

| PRJNA259854 | ENA

MAU2 and NIPBL variants in Cornelia de Lange syndrome reveal MAU2-independent loading of cohesin and uncover protective mechanisms against early truncating mutations in NIPBL

Project description:For its association with chromatin, the cohesin complex depends on a heterodimer formed by NIPBL and MAU2. Variants in NIPBL are the main cause of CdLS and result in NIPBL haploinsufficiency. Using CRISPR, we generated cells homozygous for an out-of-frame duplication in NIPBL. Remarkably, alternative translation initiation rescued NIPBL expression in these cells and produced an N-terminally truncated NIPBL that lacks MAU2-interaction domain, causing a dramatic reduction of MAU2 protein levels while a lot of NIPBL functions remain intact.

2020-06-10 | GSE122299 | GEO

RNA-seq of primary dissociated cortical Nipbl+/- neurons

Project description:RNA-seq of total RNA from Nipbl+/+ and Nipbl+/- dissociated cortical neurons at Day In Vitro (DIV10)

2021-02-28 | GSE161796 | GEO

Decreasing Wapl dosage partially corrects transcriptome phenotypes in Nipbl-/+ embryonic mouse brain

Project description:Cohesin rings interact with DNA and modulate expression of thousands of genes. NIPBL loads cohesin onto chromosomes and WAPL takes it off. Heterozygous mutations in NIPBL lead to a developmental disorder called Cornelia de Lange syndrome. Nipbl heterozygous mice are a good model for this disease. Mutations in WAPL were not known to cause disease or gene expression changes in mammals. Here we show dysregulation of >1000 genes in Wapl-/+embryonic mouse brains. The patterns of dysregulation are highly similar in Wapl and Nipbl heterozygotes, suggesting that Wapl mutations may cause disease in humans. Since WAPL and NIPBL have opposite effects on cohesin’s association with DNA, we asked whether a heterozygous Wapl mutation could correct phenotypes seen in Nipbl heterozygous mice. In fact, both gene expression and embryonic growth are partially corrected. Our data are consistent with the view that cohesin dynamics play a key role in regulating gene expression.

2022-10-11 | GSE203014 | GEO

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