PXD059191-1

PXD059191 is an original dataset announced via ProteomeXchange.

Title	Unbalanced chromatin binding of PRC1 complexes drives neurodevelopmental disorders
Description	Heterozygous de novo missense mutations in genes encoding Polycomb-group (PcG) proteins can cause diverse neurodevelopmental disorders (NDDs), but the underlying mechanisms are not yet understood. Here, we identified novel mutations in the two E3-ligases of the Polycomb Repressive complex 1 (PRC1), RING1 and RNF2, in individuals with NDDs and uncover distinct mechanisms by which PRC1 activity can be compromised. As a proof of concept, we generated embryonic stem cells (ESCs) and a novel mouse model carrying a heterozygous Rnf2 allele with a missense mutation that produces a deleterious Ring1bR70H variant. This variant causes a cell fate change in neuroprecursors (NPCs) towards the non-neuronal lineages glial and microglia. Allele-specific profiling revealed that Ring1bR70H integrates into canonical PRC1 and displaces variant PRC1 from chromatin. As a result, there is a disruption of the PRC1 balance and a deregulation of PcG target genes. We uncovered that mutant NPCs have an aberrant PcG retention and chromatin compaction pattern at key NPC pioneer factors and Wnt signaling genes. Critically, this heterozygous Rnf2 mutation in mice is sufficient to disrupt neural connectivity and structural organization in key brain regions, including the medial prefrontal cortex and hippocampus. Our findings establish Rnf2 as essential for neurodevelopmental integrity and brain function, shedding light on how PRC1 dysfunction contributes to NDDs.
HostingRepository	PRIDE
AnnounceDate	2026-04-06
AnnouncementXML	Submission_2026-04-05_16:54:07.342.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Simone Sidoli
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-12-23 11:06:58	ID requested
⏵ 1	2026-04-05 16:54:08	announced

10.1016/j.molcel.2026.01.023;

Borges RL, Gonz, á, lez-Blanco G, Arigela H, Huang Y, Caeiro LD, Fattakhov N, Lepore S, Garcia-Martinez L, Maurice M, Mehta PD, Park EJ, MacGillivray K, Nehru J, Chau M, Robayo MC, Abad C, Bilbao-Martinez A, Monteiro F, Luo X, Tan S, Bilbao D, Sidoli S, Di Stefano B, Walz K, Saltzman AL, Verdun RE, Shiekhattar R, Morey L, Unbalanced chromatin binding of Polycomb complexes drives neurodevelopmental disorders. Mol Cell, 86(4):604-624.e16(2026) [pubmed]

submitter keyword: neurodevelopment, Rnf2, PRC1,Polycomb, mutations

Simone Sidoli
contact affiliation	Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, United States
contact email	simone.sidoli@einsteinmed.edu
lab head
Simone Sidoli
contact affiliation	Albert Einstein College of Medicine
contact email	simone.sidoli@gmail.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/04/PXD059191

PRIDE project URI

• PRIDE
  1. PXD059191
     1. Label: PRIDE project
     2. Name: Unbalanced chromatin binding of PRC1 complexes drives neurodevelopmental disorders