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- Title
Neuronal genes deregulated in Cornelia de Lange Syndrome respond to removal and re-expression of cohesin.
- Authors
Weiss, Felix D.; Calderon, Lesly; Wang, Yi-Fang; Georgieva, Radina; Guo, Ya; Cvetesic, Nevena; Kaur, Maninder; Dharmalingam, Gopuraja; Krantz, Ian D.; Lenhard, Boris; Fisher, Amanda G.; Merkenschlager, Matthias
- Abstract
Cornelia de Lange Syndrome (CdLS) is a human developmental disorder caused by mutations that compromise the function of cohesin, a major regulator of 3D genome organization. Cognitive impairment is a universal and as yet unexplained feature of CdLS. We characterize the transcriptional profile of cortical neurons from CdLS patients and find deregulation of hundreds of genes enriched for neuronal functions related to synaptic transmission, signalling processes, learning and behaviour. Inducible proteolytic cleavage of cohesin disrupts 3D genome organization and transcriptional control in post-mitotic cortical mouse neurons, demonstrating that cohesin is continuously required for neuronal gene expression. The genes affected by acute depletion of cohesin belong to similar gene ontology classes and show significant numerical overlap with genes deregulated in CdLS. Interestingly, reconstitution of cohesin function largely rescues altered gene expression, including the expression of genes deregulated in CdLS. A feature of cohesin mutations in patients with Cornelia de Lange Syndrome (CdLS) is intellectual disability, but the underlying mechanisms have remained obscure. Here the authors show gene expression is deregulated in CdLS neurons and is recapitulated in a mouse model with cohesin depletion, which can be restored by re-expression of cohesin.
- Subjects
COHESINS; LABORATORY mice; NEURAL transmission; GENE expression; GENES
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-23141-9