RESUMEN
Cornelia de Lange syndrome is a multisystem developmental disorder typically caused by mutations in the gene encoding the cohesin loader NIPBL. The associated phenotype is generally assumed to be the consequence of aberrant transcriptional regulation. Recently, we identified a missense mutation in BRD4 associated with a Cornelia de Lange-like syndrome that reduces BRD4 binding to acetylated histones. Here we show that, although this mutation reduces BRD4-occupancy at enhancers it does not affect transcription of the pluripotency network in mouse embryonic stem cells. Rather, it delays the cell cycle, increases DNA damage signalling, and perturbs regulation of DNA repair in mutant cells. This uncovers a role for BRD4 in DNA repair pathway choice. Furthermore, we find evidence of a similar increase in DNA damage signalling in cells derived from NIPBL-deficient individuals, suggesting that defective DNA damage signalling and repair is also a feature of typical Cornelia de Lange syndrome.
Asunto(s)
Daño del ADN , Reparación del ADN , Síndrome de Cornelia de Lange/genética , Mutación , Animales , Proteínas de Ciclo Celular/genética , Línea Celular , Línea Celular Tumoral , Células Cultivadas , Predisposición Genética a la Enfermedad/genética , Humanos , Ratones , RNA-Seq/métodos , Transducción de Señal/genética , Factores de Transcripción/genéticaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
In the version of this article initially published, Wendy Bickmore and Madapura Pradeepa were incorrectly not indicated as corresponding authors. The error has been corrected in the HTML and PDF versions of the paper.
RESUMEN
We found that the clinical phenotype associated with BRD4 haploinsufficiency overlapped with that of Cornelia de Lange syndrome (CdLS), which is most often caused by mutation of NIPBL. More typical CdLS was observed with a de novo BRD4 missense variant, which retained the ability to coimmunoprecipitate with NIPBL, but bound poorly to acetylated histones. BRD4 and NIPBL displayed correlated binding at super-enhancers and appeared to co-regulate developmental gene expression.
Asunto(s)
Síndrome de Cornelia de Lange/genética , Mutación Missense , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Animales , Sitios de Unión/genética , Proteínas de Ciclo Celular , Células Cultivadas , Niño , Preescolar , Elementos de Facilitación Genéticos , Femenino , Regulación del Desarrollo de la Expresión Génica , Haploinsuficiencia , Humanos , Masculino , Ratones , Ratones Transgénicos , Linaje , Fenotipo , Unión ProteicaRESUMEN
Histone acetylation is generally associated with active chromatin, but most studies have focused on the acetylation of histone tails. Various histone H3 and H4 tail acetylations mark the promoters of active genes. These modifications include acetylation of histone H3 at lysine 27 (H3K27ac), which blocks Polycomb-mediated trimethylation of H3K27 (H3K27me3). H3K27ac is also widely used to identify active enhancers, and the assumption has been that profiling H3K27ac is a comprehensive way of cataloguing the set of active enhancers in mammalian cell types. Here we show that acetylation of lysine residues in the globular domain of histone H3 (lysine 64 (H3K64ac) and lysine 122 (H3K122ac)) marks active gene promoters and also a subset of active enhancers. Moreover, we find a new class of active functional enhancers that is marked by H3K122ac but lacks H3K27ac. This work suggests that, to identify enhancers, a more comprehensive analysis of histone acetylation is required than has previously been considered.
