Joyce Wolf van der Meer1,8, Axelle Larue2,8, Jan A. van der Knaap1, Gillian E. Chalkley1, Ayestha Sijm1, Leila Beikmohammadi1,6, Elena N. Kozhevnikova1,7, Aniek van der Vaart1, Ben C. Tilly1, Karel Bezstarosti1,3, Dick H.W. Dekkers1,3, Wouter A.S. Doff1,3, P. Jantine van de Wetering-Tieleman1,3, Kristina Lanko4, Tahsin Stefan Barakat4, Tim Allertz5, Jeffrey van Haren5, Jeroen A.A. Demmers1,3, Yaser Atlasi2 and C. Peter Verrijzer1 1Department of Biochemistry, Erasmus University Medical Center, 3025 GD Rotterdam, The Netherlands; 2Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast BT9 7AE, United Kingdom; 3Proteomics Center, Erasmus MC University Medical Center, 3025 GD Rotterdam, The Netherlands; 4Department of Clinical Genetics, Erasmus MC University Medical Center, 3025 GD Rotterdam, The Netherlands; 5Department of Cell Biology, Erasmus University Medical Center, 3025 GD Rotterdam, The Netherlands Corresponding authors: c.verrijzererasmusmc.nl, j.demmerserasmusmc.nl, y.atlasiqub.ac.uk

↵8 These authors contributed equally to this work.

↵Present addresses: 6Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands; 7Laboratory of Human Disease Models, Institute of Molecular and Cellular Biology, Novosibirsk, Russia.

Abstract

Pathogenic variants in the ubiquitin-specific protease 7 (USP7) gene cause a neurodevelopmental disorder called Hao-Fountain syndrome. However, it remains unclear which of USP7's pleiotropic functions are relevant for neurodevelopment. Here, we present a combination of quantitative proteomics, transcriptomics, and epigenomics to define the USP7 regulatory circuitry during neuronal differentiation. USP7 activity is required for the transcriptional programs that direct both the differentiation of embryonic stem cells into neural stem cells and the neuronal differentiation of SH-SY5Y neuroblastoma cells. USP7 controls the dosage of the Polycomb monubiquitylated histone H2A lysine 119 (H2AK119ub1) ubiquitin ligase complexes ncPRC1.1 and ncPRC1.6. Loss-of-function experiments revealed that BCOR–ncPRC1.1, but not ncPRC1.6, is a key effector of USP7 during neuronal differentiation. Indeed, BCOR–ncPRC1.1 mediates a major portion of USP7-dependent gene regulation during this process. Besides providing a detailed map of the USP7 regulome during neurodifferentiation, our results suggest that USP7- and ncPRC1.1-associated neurodevelopmental disorders involve dysregulation of a shared epigenetic network.

Received September 4, 2024. Accepted January 15, 2025.