BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange–like syndrome

Olley, Gabrielle; Ansari, Morad; Bengani, Hemant; Grimes, Graeme R.; Rhodes, James; Kriegsheim, Alex von; Blatnik, Ana; Stewart, Fiona; Wakeling, Emma; Carroll, Nicola; Ross, Alison; Park, Soo‐Mi; Study, Deciphering Developmental Disorders; Bickmore, Wendy A.; Pradeepa, Madapura M.; FitzPatrick, David R.

doi:10.1038/s41588-018-0042-y

Cited by 105 publications

(134 citation statements)

References 37 publications

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“…Mutations in the STAG2 gene encoding SA2 cause intellectual and growth deficits overlapping those seen in cohesinopathies caused by mutations in NIPBL or cohesin subunit genes (Mullegama et al 2017, Soardi et al 2017, Mullegama et al 2018, Yuan et al 2018. Individuals with BRD4 mutations display similar birth defects, and BRD4 and NIPBL co-localize at enhancers (Olley et al 2018). These studies agree with our findings that SA and Fs(1)h facilitate association of Nipped-B and Rad21 with enhancers and that Fs(1)h and Nipped-B function together in development.…”

Section: Parallels With Vertebrate Cohesinsupporting

confidence: 90%

“…Mammalian Mediator interacts with NIPBL (Nipped-B) (Kagey et al 2010) and an affinity chromatography-mass spectrometry screen revealed that the Drosophila MED30 Mediator subunit interacts with Nipped-B (Guruharsha et al 2012). It was recently reported that human BRD4 interacts with NIPBL and that BRD4 mutations cause birth defects similar to those caused by NIPBL mutations (Olley et al 2018).…”

Section: The Med30 Mediator Subunit and The Fs(1)h Bet Domain Proteinmentioning

confidence: 99%

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Cohesin occupancy and composition at enhancers and promoters are linked to DNA replication origin proximity inDrosophila

Pherson

Misulovin

Gause

et al. 2019

Preprint

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Cohesin consists of the Smc1-Smc3-Rad21 tripartite ring and the SA protein that interacts with Rad21. The Nipped-B protein loads cohesin topologically around chromosomes to mediate sister chromatid cohesion and facilitate long-range control of gene transcription. It is largely unknown how Nipped-B and cohesin associate specifically with gene promoters and transcriptional enhancers, or how sister chromatid cohesion is established. Here we use genome-wide chromatin immunoprecipitation in Drosophila cells to show that SA and the Fs(1)h (BRD4) BET domain protein help recruit Nipped-B and cohesin to enhancers and DNA replication origins, while the MED30 subunit of the Mediator complex directs Nipped-B and Rad21 to promoters. All enhancers and their neighboring promoters are close to DNA replication origins and bind SA with proportional levels of cohesin subunits. Most promoters are far from origins and lack SA, but bind Nipped-B and Rad21 with sub-proportional amounts of Smc1, indicating that they bind SA-deficient cohesin part of the time. Genetic data confirm that Nipped-B and Rad21 function together with Fs(1)h in vivo to facilitate Drosophila development. These findings demonstrate that Nipped-B and cohesin are differentially targeted to enhancers and promoters and suggest models for how SA and DNA replication help establish sister chromatid cohesion and facilitate enhancer-promoter communication. They indicate that SA is not an obligatory cohesin subunit but a factor that controls cohesin location on chromosomes.

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Section: Parallels With Vertebrate Cohesinsupporting

confidence: 90%

Section: The Med30 Mediator Subunit and The Fs(1)h Bet Domain Proteinmentioning

confidence: 99%

Cohesin occupancy and composition at enhancers and promoters are linked to DNA replication origin proximity inDrosophila

Pherson

Misulovin

Gause

et al. 2019

Preprint

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“…Moreover, multiple next‐generation sequencing (NGS) technologies identified mutations in key chromatin‐associated factors, genetically different from cohesin, in patients presenting features of CdLS or CdLS‐like phenotype. These mutations affect genes coding for methyltransferases such as KMT2A , for subunits of the chromatin‐remodeler SWItch/sucrose non‐fermentable (SWI/SNF) complex and for transcriptional regulators such as EP300 , AFF4 , ANKRD11 , SETD5 or the Bromodomain‐containing protein 4 BRD4 gene, encoding a chromatin‐associated protein . In Figure the facial dysmorphisms associated with the genes mentioned above are shown and clinical features associated with mutations in these genes are summarized in Table .…”

Section: Chromatin Regulation and Cdls: Clinical And Genetic Featuresmentioning

confidence: 99%

“…Classical facial dysmorphisms of CdLS and related overlapping syndromes. Patient's representation in the middle of the figure displays typical CdLS phenotype with mutations in NIPBL (representative of classic CdLS dysmorphisms); all the other patients' representations surrounding NIPBL display all the related phenotypic variants that overlap with the classic CdLS: AFF4 , ANKRD11 , KMT2A , SETD5 , EP300 , BRD4 , SWI/SNF . CdLS, Cornelia de Lange syndrome [Colour figure can be viewed at wileyonlinelibrary.com]…”

Section: Chromatin Regulation and Cdls: Clinical And Genetic Featuresmentioning

confidence: 99%

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Chromatinopathies: A focus on Cornelia de Lange syndrome

et al. 2019

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In recent years, many genes have been associated with chromatinopathies classified as “Cornelia de Lange Syndrome‐like.” It is known that the phenotype of these patients becomes less recognizable, overlapping to features characteristic of other syndromes caused by genetic variants affecting different regulators of chromatin structure and function. Therefore, Cornelia de Lange syndrome diagnosis might be arduous due to the seldom discordance between unexpected molecular diagnosis and clinical evaluation. Here, we review the molecular features of Cornelia de Lange syndrome, supporting the hypothesis that “CdLS‐like syndromes” are part of a larger “rare disease family” sharing multiple clinical features and common disrupted molecular pathways.

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Cohesin — bridging the gap among gene transcription, genome stability, and human diseases

Di Nardo,

Musio

2024

FEBS Letters

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The intricate landscape of cellular processes governing gene transcription, chromatin organization, and genome stability is a fascinating field of study. A key player in maintaining this delicate equilibrium is the cohesin complex, a molecular machine with multifaceted roles. This review presents an in‐depth exploration of these intricate connections and their significant impact on various human diseases.

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BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange–like syndrome

Cited by 105 publications

References 37 publications

Cohesin occupancy and composition at enhancers and promoters are linked to DNA replication origin proximity inDrosophila

Cohesin occupancy and composition at enhancers and promoters are linked to DNA replication origin proximity inDrosophila

Chromatinopathies: A focus on Cornelia de Lange syndrome

Cohesin — bridging the gap among gene transcription, genome stability, and human diseases

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