Transcription Factors Recruit the Cohesin Loader NIPBL to Promote Chromatin Looping and Long-range Gene Regulation
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ABSTRACT:
PROVIDER: PRJNA682404 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR13192948_1.fastq.gz | Fastqsanger.gz | |||
| SRR13192948_2.fastq.gz | Fastqsanger.gz | |||
| SRR13192949_1.fastq.gz | Fastqsanger.gz | |||
| SRR13192949_2.fastq.gz | Fastqsanger.gz |
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Project description:The cohesin complex is central to chromatin looping, but mechanisms by which these long-range chromatin interactions are formed and persist remain unclear. We demonstrate that interactions between a transcription factor and the cohesin loader NIPBL regulate enhancer-promoter looping and promote long-range gene regulation. Using mass-spectrometry, genome mapping, and single-molecule tracking methods, we demonstrate that NIPBL and cohesin regulate the dynamics and function of the glucocorticoid receptor (GR). Moreover, glucocorticoid treatment stabilizes NIPBL and cohesin interactions by promoting loop extrusion and chromatin looping. Patient-derived acute myeloid leukemia cells harboring cohesin mutations exhibit a reduced response to glucocorticoids (GCs), suggesting that the GR-NIPBL-cohesin interaction is defective in these patients, and they may be poor candidates for GC treatment.
2021-06-01 | GSE162617 | GEO
Project description:While the cohesin complex is a key player in genome architecture, how it localizes to specific chromatin sites is not well understood. Recently, we and others have proposed that direct interactions with transcription factors (TFs) lead to the localization of the cohesin-loader complex (NIPBL/MAU2) within enhancers. Here, we identify two clusters of protein-protein interaction (PPI) motifs within the NIPBL sequence that regulate NIPBL dynamics, interactome, and NIPBL-dependent transcriptional programs. These PPIMs directly interact with chromatin-associated proteins, including TFs and one of them is necessary for the maintenance of the NIPBL-MAU2 heterodimer. Finally, using the glucocorticoid receptor (GR) as a model, we investigate its interaction surfaces with NIPBL and MAU2 using AlphaFold2 and surface plasmon resonance to uncover a TF-NIPBL-MAU2 ternary complex and present its importance in GR-dependent gene regulation.
2025-04-17 | PXD058574 | Pride
Project description:The cohesin complex is a key player in dynamic genome architecture adjustments. The loading of the cohesin complex on chromatin is believed to be achieved by the cohesin-loader Nipped-B homolog (NIPBL). Recently, we and others proposed that direct interactions with transcriptions factors (TFs) would lead to accurate positioning of NIPBL on the DNA. In this study, we identified remarkable protein-protein interaction motifs (PPIMs) in the NIPBL sequence. Mutations of those motifs dramatically alters: (i) the global NIPBL chromatin binding, (ii) the NIPBL-dependent transcriptional program and (iii) the NIPBL proteome network including TFs. While we found that the MAU2/NIPBL interaction was relying on those PPIMs, we further discovered that MAU2 was directly interacting with dozens of TFs. Concomitantly, we found that numerous TFs were also able to interact with NIPBL through PPIMs. Finally, using nuclear receptors as models and then focusing on the Glucocorticoid Receptor (GR), we mechanistically dissect a trimeric complex formed by GR, NIPBL and MAU2 and investigate the importance of those interactions for GR transcriptional program.
2025-04-16 | GSE282583 | GEO
Project description:The Mediator and Cohesin complexes control the cellular transcriptional program. However, it is not well understood how they are recruited to regulatory regions. Our study shows that the core transcriptional regulatory circuitry of cancer cells is essential to recruit Mediator, Cohesin and NIPBL to enhancer and promoter regions of actively transcribed genes in cancer cells. ChIP-seq analysis of Mediator (MED1), Cohesin (SMC1A) and NIPBL in HEPG2, A549 and MCF7 cells. The analysis also includes ChIP-Seq data for the transcription factor ERa in MCF7 cells treated with estradiol.
2016-10-24 | E-GEOD-76893 | biostudies-arrayexpress
Project description:Cohesin mediates sister chromatid cohesion and organizes the genome through the formation of chromatin loops. Two versions of the complex carrying either STAG1 or STAG2 show overlapping and specific functions and both are required to fulfill embryonic development. Cohesin-STAG1 displays longer residence time on chromatin that depends on CTCF and ESCO1 and establishes longer, long-lived chromatin loops together with CTCF. Cohesin-STAG2 shows a preferential interaction with WAPL and mediates shorter loops involved in tissue-specific transcription independently of CTCF. Here we show that the two variants respond in opposite ways to knock down of NIPBL, the putative cohesin loader that is also essential for loop extrusion. Cohesin-STAG1 levels increase on chromatin under this condition and the complex accumulates further at CTCF positions while cohesin-STAG2 is diminished genome-wide. Our data support a model in which NIPBL is not required for association of cohesin with chromatin but it is for loop extrusion, which in turn facilitates stabilization of cohesin-STAG2 at CTCF positions after being loaded elsewhere. In contrast, cohesin-STAG1 is preferentially loaded at CTCF sites independently of NIPBL. Nevertheless, loop formation by these chromatin-bound complexes is impaired and gene expression is severely affected, resembling alterations in Cornelia de Lange patients
2023-01-30 | GSE207115 | GEO
Project description:Cohesin mediates sister chromatid cohesion and organizes the genome through the formation of chromatin loops. Two versions of the complex carrying either STAG1 or STAG2 show overlapping and specific functions and both are required to fulfill embryonic development. Cohesin-STAG1 displays longer residence time on chromatin that depends on CTCF and ESCO1 and establishes longer, long-lived chromatin loops together with CTCF. Cohesin-STAG2 shows a preferential interaction with WAPL and mediates shorter loops involved in tissue-specific transcription independently of CTCF. Here we show that the two variants respond in opposite ways to knock down of NIPBL, the putative cohesin loader that is also essential for loop extrusion. Cohesin-STAG1 levels increase on chromatin under this condition and the complex accumulates further at CTCF positions while cohesin-STAG2 is diminished genome-wide. Our data support a model in which NIPBL is not required for association of cohesin with chromatin but it is for loop extrusion, which in turn facilitates stabilization of cohesin-STAG2 at CTCF positions after being loaded elsewhere. In contrast, cohesin-STAG1 is preferentially loaded at CTCF sites independently of NIPBL. Nevertheless, loop formation by these chromatin-bound complexes is impaired and gene expression is severely affected, resembling alterations in Cornelia de Lange patients
2023-01-30 | GSE207113 | GEO
Project description:Cohesin mediates sister chromatid cohesion and organizes the genome through the formation of chromatin loops. Two versions of the complex carrying either STAG1 or STAG2 show overlapping and specific functions and both are required to fulfill embryonic development. Cohesin-STAG1 displays longer residence time on chromatin that depends on CTCF and ESCO1 and establishes longer, long-lived chromatin loops together with CTCF. Cohesin-STAG2 shows a preferential interaction with WAPL and mediates shorter loops involved in tissue-specific transcription independently of CTCF. Here we show that the two variants respond in opposite ways to knock down of NIPBL, the putative cohesin loader that is also essential for loop extrusion. Cohesin-STAG1 levels increase on chromatin under this condition and the complex accumulates further at CTCF positions while cohesin-STAG2 is diminished genome-wide. Our data support a model in which NIPBL is not required for association of cohesin with chromatin but it is for loop extrusion, which in turn facilitates stabilization of cohesin-STAG2 at CTCF positions after being loaded elsewhere. In contrast, cohesin-STAG1 is preferentially loaded at CTCF sites independently of NIPBL. Nevertheless, loop formation by these chromatin-bound complexes is impaired and gene expression is severely affected, resembling alterations in Cornelia de Lange patients
2023-01-30 | GSE207110 | 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:The relationship between cohesin-mediated chromatin looping and gene expression remains unclear. NIPBL and WAPL are two opposing regulators of cohesin activity; depletion of either is associated with changes in both chromatin folding and transcription across a wide range of cell types. However, a direct comparison of their individual and combined effects on gene expression in the same cell type is lacking. We find that NIPBL or WAPL depletion in human HCT116 cells each alter the expression of ~2,000 genes, with only ~30% of the genes shared between the conditions. We find that clusters of differentially expressed genes within the same topologically associated domain (TAD) show coordinated misexpression, suggesting some genomic domains are especially sensitive to either more or less cohesin. Finally, co-depletion of NIPBL and WAPL restores the majority of gene misexpression as compared to either knockdown alone. A similar set of NIPBL-sensitive genes are rescued following CTCF co-depletion. Together, this indicates that altered transcription due to reduced cohesin activity can be functionally offset by removal of either its negative regulator (WAPL) or the physical barriers (CTCF) that restrict loop-extrusion events.
2022-11-03 | GSE200773 | GEO
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