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Genome occupancy of NIPBL in mouse P19 teratocarcinoma cells.

ABSTRACT: Mutations in NIPBL are the major cause of Cornelia de Lange Syndrome (CdLS). NIPBL is the cohesin loading factor and has recently been associated with the BET (Bromodomains and Extra Terminal (ET) domain) proteins BRD2 and BRD4. Related to this, a CdLS-like phenotype has been described associated to BRD4 mutations. We have study the genomic occupancy of NIPBL in mouse P19 teratocarcinoma cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE132784 | GEO | 2020/01/01

REPOSITORIES: GEO

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Transcriptome analysis upon Nipbl, Brd2 and Brd4 knockdown in P19 cells

Project description:Mutations in NIPBL are the major cause of Cornelia de Lange Syndrome (CdLS). NIPBL is the cohesin loading factor and has recently been associated with the BET (Bromodomains and Extra Terminal (ET) domain) proteins BRD2 and BRD4. Related to this, a CdLS-like phenotype has been described associated to BRD4 mutations. To understand the relationship between NIPBL and BET proteins, we have performed RNA-Seq expression analysis following depletion of the different proteins in mouse P19 teratocarcinoma cells. Results indicate that genes regulated by NIPBL largely overlap with those regulated by BRD4 but not with those regulated by BRD2.

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Gastrulation-stage gene expression in Nipbl+/- mouse embryos foreshadows the development of syndromic birth defects

Project description:In animal models, Nipbl-deficiency phenocopies gene expression changes and birth defects seen in Cornelia de Lange Syndrome (CdLS), the most common cause of which is Nipbl-haploinsufficiency. Previous studies in Nipbl+/- mice identified aberrant gene expression and heart defects as early as cardiac crescent (CC) stage. Here, we performed single-cell RNA-sequencing on wildtype (WT) and Nipbl+/- mouse embryos at CC- and earlier (gastrulation) stages. Nipbl+/- embryos had fewer mesoderm cells than WT and altered proportions of mesodermal cell subpopulations. These findings were associated with an underexpression of genes implicated in driving specific mesodermal lineages. Nipbl+/- embryos also misexpressed developmentally-critical genes, including the transcription factor, Nanog, and genes governing left-right and anterior-posterior patterning. These events of cell misallocation and transcriptional dysregulation foreshadowed defects in tissue composition and patterning that arise later in Nipbl+/- mice, offering insights into early developmental contributions to birth defects in CdLS.

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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.

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Genome occupancy of NIPBL in mouse P19 teratocarcinoma cells.

Project description:Genome occupancy of NIPBL in mouse P19 teratocarcinoma cells.

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Cornelia-de-Lange syndrome associated mutations cause a DNA damage signalling and repair defect

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