Genome-wide transcriptome analysis of NIPBL hematopoeitic progenitors and megakaryocytes
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ABSTRACT:
PROVIDER: PRJNA490377 | ENA |
REPOSITORIES: ENA
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Project description:The purpose of this study was to compare the transcriptome of NIPBL patient derived Hematopoietic progenitors and patient-derived megakaryocytes to healthy unaffected individuals Methods: HPC transcriptome profiles of three CdLS patient iPSCs harboring mutations in the NIPBL gene and megakaryocytes generated from patient-iPSCS were generated by deep sequencing, in triplicate, using Illumina HiSeq 2500. The sequence reads that passed quality filters were analyzed at the transcript isoform level with two methods: Burrows–Wheeler Aligner (BWA) followed by ANOVA (ANOVA) and TopHat followed by Cufflinks. Results: Using an optimized data analysis workflow, we mapped about 15 million sequence reads per sample to the human genome and identified transcripts in CdLS-HPCs and transcripts in CdLS-MEGs. Conclusion: Our data supports dysregulation of megakaroyctye maturation and growth arrest in response to multiple conserved developmental pathways.
2019-11-01 | GSE119828 | GEO
Project description:The purpose of this study was to compare the transcriptome of NIPBL patient derived iPSCs and patient-derived cardiomyocytes to healthy unaffected individuals Methods: iPSC transcriptome profiles of three CdLS patient iPSCs harboring mutations in the NIPBL gene and cardiomyocytes derived from patient-iPSCS were generated by deep sequencing, in triplicate, using Illumina XXXXXX. The sequence reads that passed quality filters were analyzed at the transcript isoform level with two methods: Burrows–Wheeler Aligner (BWA) followed by ANOVA (ANOVA) and TopHat followed by Cufflinks. Results: Using an optimized data analysis workflow, we mapped about 15 million sequence reads per sample to the human genome and identified XXXX transcripts in CdLS-iPSCs and XXXXXX transcripts in control-iPSCs with XXXX workflow. Conclusion: Our data is the represents the first human developmental model for studying CdLS through pluripotent stem cells and lineage commited subtypes (cardiomyocytes). This data highlights NIPBLs role in regulating transcriptional regulation and has significant consequences on DNA nucleosome involvement as it relates to global gene expression. This work provides preliminary evidence that NIPBL is required for normal epigenetic and DNA landscape establishment during embryonic cardiomyocyte generation.
2018-02-22 | GSE102873 | GEO
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
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.
2020-01-01 | GSE132785 | GEO
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
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
Project description:RNA-seq of total RNA from Nipbl+/+ and Nipbl+/- dissociated cortical neurons at Day In Vitro (DIV10)
2021-02-28 | GSE161796 | GEO
Project description:ChIP-seq assay was performed with anti-p45 antibody using in vitro cultured primary megakaryocytes to identify direct p45 target genes in megakaryocytes. This analysis revealed genes that regulate platelet function, which were not known previously to be p45-regulated. ChIP was performed using a day-3 primary culture of megakaryocytes from E13.5 fetal livers of wild-type mice with an anti-p45 antibody.
2013-11-01 | E-GEOD-42249 | biostudies-arrayexpress
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
Project description:The gene expression program is regulated by a cell-type specific chromosome architecture. The connection between enhancer and promoter regions is dependent on a protein complex containing Nipbl, Mediator and Cohesin. To gain insights into the chromosome architecture of human differentiated cells, we profiled NIPBL and SMC1 in lymphoblastoid cells (LCLs). DNA was enriched from hLCLs and chromatin immunoprecipitations (ChIPs) were analyzed by Solexa sequencing. ChIPs were performed using an antibody against NIPBL and SMC1. Whole cell extract is provided for background.
2012-06-01 | E-GEOD-38395 | biostudies-arrayexpress