PROSER1 modulates DNA demethylation through dual mechanisms to prevent syndromic developmental malformations
Author(s)
Type
Journal Article
Abstract
The link between DNA methylation and neurodevelopmental disorders is well established. However, how DNA methylation is fine-tuned—ensuring precise gene expression and developmental fidelity—remains poorly understood. PROSER1, a known TET2 interactor, was recently linked to a severe neurodevelopmental disorder. Here, we demonstrate that PROSER1 interacts with all TET enzymes and stabilizes chromatin-bound TET–OGT–PROSER1–DBHS (TOPD) complexes, which regulate DNA demethylation and developmental gene expression. Surprisingly, we found that PROSER1 also sequesters TET enzymes, preventing widespread demethylation and transposable element derepression. Our findings identify PROSER1 as a key factor that both positively and negatively regulates DNA demethylation essential for mammalian neurodevelopment.
Date Issued
2024-11-01
Date Acceptance
2024-10-15
Citation
Genes & Development, 2024, 38 (21-24), pp.952-964
ISSN
0890-9369
Publisher
Cold Spring Harbor Laboratory Press
Start Page
952
End Page
964
Journal / Book Title
Genes & Development
Volume
38
Issue
21-24
Copyright Statement
© 2024 Fleming et al.; Published by Cold Spring Harbor Laboratory Press This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/39562138
PII: gad.352176.124
Subjects
Cell Biology
development
Developmental Biology
DIFFERENTIATION
DNA methylation
Genetics & Heredity
HEMATOPOIETIC STEM-CELLS
INTELLECTUAL DISABILITY
LEADS
Life Sciences & Biomedicine
METHYLATION
neurodevelopmental disorder
NONO
PROTEINS
Science & Technology
START SITES
TET1
TET2
TET3
TOPD
TRANSCRIPTION
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2024-11-19