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BRD4 orchestrates genome folding to promote neural crest progenitor differentiation

ABSTRACT: Higher-order chromatin structure is critical for proper gene regulation, but the relationship between genome folding and cellular identity remains elusive. Here, we show that genetic deletion of the Bromodomain-containing protein 4 (BRD4) in murine neural crest cells recapitulates features of cohesinopathies. We demonstrate that BRD4 interacts with NIPBL, a positive cohesin regulator, and acute depletion of BRD4 or loss of the BRD4-NIPBL interaction reduces NIPBL-occupancy, elucidating the importance of BRD4 in stabilizing NIPBL on chromatin. Genome-wide chromatin interaction mapping and quantitative imaging studies demonstrate that BRD4-depletion results in aberrant genome folding, specifically loss of a subset of chromatin loops, weakening of TADs, and compromised loop extrusion. Finally, loss of BRD4 or the interaction with NIPBL impedes neural crest differentiation which, remarkably, is rescued by WAPL depletion, a negative cohesin regulator. Our data reveal that BRD4 choreographs genome folding, illustrating the importance of balancing cohesin activity on progenitor differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE169516 | GEO | 2021/07/16

REPOSITORIES: GEO

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Co-depletion of NIPBL and WAPL balance cohesin activity to correct gene misexpression

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

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.

2020-01-01 | GSE132785 | GEO

Transcription Factors Recruit the Cohesin Loader NIPBL to Promote Chromatin Looping and Long-range Gene Regulation

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

Response of cohesin STAG1 and STAG2 to reduction of NIPBL levels [Hi-C]

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

Response of cohesin STAG1 and STAG2 to reduction of NIPBL levels [ChIP-Seq]

2023-01-30 | GSE207113 | GEO

Response of cohesin STAG1 and STAG2 to reduction of NIPBL levels [RNA-Seq]

2023-01-30 | GSE207110 | GEO

Genome occupancy of NIPBL in mouse P19 teratocarcinoma cells.

2020-01-01 | GSE132784 | GEO

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

The cohesin acetylation cycle controls chromatin loop length through a PDS5A brake mechanism

Project description:Cohesin structures the genome through the formation of chromatin loops and by holding together the sister chromatids. The acetylation of cohesin’s SMC3 subunit is a dynamic process that involves the acetyltransferase ESCO1 and deacetylase HDAC8. Here we show that this cohesin acetylation cycle controls the 3D genome. ESCO1 restricts the length of chromatin loops and architectural stripes, while HDAC8 promotes the extension of such loops and stripes. This role in controlling loop length turns out to be distinct from the canonical role of cohesin acetylation that protects against WAPL-mediated DNA release. We reveal that acetylation rather controls cohesin’s interaction with PDS5A to restrict chromatin loop length. Our data supports a model in which this PDS5A-bound state acts as a brake that enables the pausing and restart of loop enlargement. The cohesin acetylation cycle hereby provides punctuation in the process of genome folding.

2022-03-14 | PXD032185 | Pride

The structural basis for cohesin/CTCF anchored loops [ChIP-seq]

Project description:Cohesin catalyses the folding of the genome into loops that are anchored by CTCF. The molecular mechanism of how cohesin and CTCF structure the 3D genome has remained unclear. Here we show that a segment within the CTCF N terminus interacts with the SA2-SCC1 subunits of cohesin. A 2.6 Å crystal structure of SA2-SCC1 in complex with CTCF reveals the molecular basis of the interaction. We demonstrate that this interaction is specifically required for CTCF-anchored loops and contributes to the positioning of cohesin at CTCF-binding sites. A similar motif is present in a number of established and novel cohesin ligands, including the cohesin release factor WAPL. Our data suggest that CTCF enables chromatin loop formation by protecting cohesin against loop release. These results provide fundamental insights into the molecular mechanism that enables dynamic regulation of chromatin folding by cohesin and CTCF.

2020-01-07 | GSE126634 | GEO

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