PUBLICATION

Loss of the crumbs cell polarity complex disrupts epigenetic transcriptional control and cell cycle progression in the developing retina

Authors
Owen, N., Toms, M., Tian, Y., Toualbi, L., Richardson, R., Young, R., Tracey-White, D., Dhami, P., Beck, S., Moosajee, M.
ID
ZDB-PUB-230120-2
Date
2023
Source
The Journal of pathology   259(4): 441-454 (Journal)
Registered Authors
Young, Rodrigo
Keywords
DNA methylation, Polarity complex, RNA-seq, epigenome, iPSC, retina, transcriptome, zebrafish
Datasets
GEO:GSE178709, GEO:GSE178842
MeSH Terms
  • Animals
  • Cell Cycle
  • Cell Polarity*/genetics
  • Epigenesis, Genetic
  • Eye Proteins/genetics
  • Eye Proteins/metabolism
  • Humans
  • Membrane Proteins/metabolism
  • Nerve Tissue Proteins/metabolism
  • Retina/metabolism
  • Zebrafish*/genetics
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed
36656098 Full text @ J. Pathol.
Abstract
The crumbs cell polarity complex plays a crucial role in apical-basal epithelial polarity, cellular adhesion, and morphogenesis. Homozygous variants in human CRB1 result in autosomal recessive Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP), with no established genotype-phenotype correlation. The associated protein complexes have key functions in developmental pathways; however the underlying disease mechanism remains unclear. Using the oko meduzym289/m289 (crb2a-/- ) zebrafish, we performed integrative transcriptomic (RNA-seq data) and methylomic (reduced representation bisulphite sequencing, RRBS) analysis of whole retina to identify dysregulated genes and pathways. Delayed retinal cell specification was identified in both the crb2a-/- zebrafish and CRB1 patient-derived retinal organoids, highlighting dysfunction of cell cycle modulation and epigenetic transcriptional control. Differential DNA methylation analysis revealed novel hypermethylated pathways involving biological adhesion, Hippo and transforming growth factor β (TGFβ) signalling. By integrating gene expression with DNA methylation using functional epigenetic modules (FEM), we identified 6 key modules involving cell cycle control and disturbance of TGFβ, BMP, Hippo, and SMAD protein signal transduction pathways, revealing significant interactome hotspots relevant to crb2a function, confirming the epigenetic control of gene regulation in early retinal development and points to a novel mechanism underlying CRB1-retinopathies. This article is protected by copyright. All rights reserved.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping