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.

Details

Title
Neuronal genes deregulated in Cornelia de Lange Syndrome respond to removal and re-expression of cohesin
Author
Weiss, Felix D 1   VIAFID ORCID Logo  ; Calderon Lesly 2 ; Yi-Fang, Wang 3 ; Georgieva Radina 4   VIAFID ORCID Logo  ; Guo, Ya 5 ; Cvetesic Nevena 6   VIAFID ORCID Logo  ; Kaur Maninder 7 ; Dharmalingam Gopuraja 3 ; Krantz, Ian D 8 ; Lenhard Boris 9   VIAFID ORCID Logo  ; Fisher, Amanda G 10   VIAFID ORCID Logo  ; Merkenschlager Matthias 10   VIAFID ORCID Logo 

 Imperial College London, Lymphocyte Development Group, Epigenetics Section, MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Faculty of Medicine, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111); University of Bonn, Institute of Innate Immunity, Bonn, Germany (GRID:grid.10388.32) (ISNI:0000 0001 2240 3300) 
 Imperial College London, Lymphocyte Development Group, Epigenetics Section, MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Faculty of Medicine, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111); Research Institute of Molecular Pathology, Vienna, Austria (GRID:grid.14826.39) (ISNI:0000 0000 9799 657X) 
 Imperial College London, MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Faculty of Medicine, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111) 
 Imperial College London, Lymphocyte Development Group, Epigenetics Section, MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Faculty of Medicine, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111); Imperial College London, Computational Regulatory Genomics Group, Epigenetics Section, MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Faculty of Medicine, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111) 
 Imperial College London, Lymphocyte Development Group, Epigenetics Section, MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Faculty of Medicine, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111); Shanghai Jiao Tong University, School of Life Sciences and Biotechnology, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
 Imperial College London, Computational Regulatory Genomics Group, Epigenetics Section, MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Faculty of Medicine, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111) 
 The Children’s Hospital of Philadelphia, Division of Human Genetics, The Department of Pediatrics, Philadelphia, USA (GRID:grid.239552.a) (ISNI:0000 0001 0680 8770) 
 The Children’s Hospital of Philadelphia, Division of Human Genetics, The Department of Pediatrics, Philadelphia, USA (GRID:grid.239552.a) (ISNI:0000 0001 0680 8770); The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); The Children’s Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, Philadelphia, USA (GRID:grid.239552.a) (ISNI:0000 0001 0680 8770) 
 Imperial College London, Computational Regulatory Genomics Group, Epigenetics Section, MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Faculty of Medicine, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111); University of Bergen, Sars International Centre for Marine Molecular Biology, Bergen, Norway (GRID:grid.7914.b) (ISNI:0000 0004 1936 7443) 
10  Imperial College London, Lymphocyte Development Group, Epigenetics Section, MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Faculty of Medicine, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2531842167
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.