Neuronal genes deregulated in Cornelia de Lange Syndrome respond to removal and re-expression of cohesin

Felix D Weiss,Amanda G Fisher,Nevena Cvetesic,Matthias Merkenschlager,Boris Lenhard,Maninder Kaur,Yi-Fang Wang,Ya Guo,Gopuraja Dharmalingam,Lesly Calderon,Radina Georgieva,Ian D Krantz

doi:10.1038/s41467-021-23141-9

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.

Highlights

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
Aberrant gene expression is a likely cause of neuronal dysfunction in CdLS, studies of gene expression in CdLS patient cells have to date been limited to induced pluripotent stem cells[35], cardiac[35] and lymphoblastoid cells[31]
Three of the patients had heterozygous mutations in NIPBL, the gene most frequently mutated in CdLS

Summary

Introduction

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. 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. While the loss of cohesin affects the transcription of a limited number of genes, enhancer-associated[7,13] and inducible genes[14], including neuronal activity-dependent genes[15], are frequently deregulated when 3D organization is perturbed by the loss of cohesin. We establish experimental models that allow for the inducible degradation of the cohesin subunit RAD21 in post-mitotic primary cortical mouse neurons These reveal that cohesin is continuously required to sustain neuronal gene expression. The expression of these genes is rescued by reconstitution of functional cohesin, indicating that at least some of these changes may be reversible

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Results

Conclusion