Abstract
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.
Highlights
IntroductionWe identified a missense mutation in BRD4 associated with a Cornelia de Lange-like syndrome that reduces BRD4 binding to acetylated histones
Cornelia de Lange syndrome is a multisystem developmental disorder typically caused by mutations in the gene encoding the cohesin loader NIPBL
To gain further insights into the mechanisms underlying Cornelia de Lange syndrome (CdLS), and the role of BRD4, we investigated the phenotype of mouse embryonic stem cells homozygous for the orthologous amino acid substitution in mouse Brd[4] ( p.Tyr431Cys but for simplicity here termed Brd4Y430C)
Summary
We identified a missense mutation in BRD4 associated with a Cornelia de Lange-like syndrome that reduces BRD4 binding to acetylated histones. 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. Mutations in genes encoding chromatin regulators unrelated to cohesin, such as ANKRD11, KMT2A, AFF4 and the bromodomain and extraterminal domain (BET) protein BRD4, have been reported to cause CdLS-like phenotypes[1] suggesting that chromatin dysregulation may play a role in CdLS as well. We show increased foci of the downstream effectors of 53BP1, Rif[1] and the
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