Owen, Nicholas;
Toms, Maria;
Tian, Yuan;
Toualbi, Lyes;
Richardson, Rose;
Young, Rodrigo;
Tracey-White, Dhani;
... Moosajee, Mariya; + view all
(2023)
Loss of the crumbs cell polarity complex disrupts epigenetic transcriptional control and cell cycle progression in the developing retina.
The Journal of Pathology
, 259
pp. 441-454.
10.1002/path.6056.
Preview |
Text
Beck_The Journal of Pathology - 2023 - Owen - Loss of the crumbs cell polarity complex disrupts epigenetic transcriptional.pdf Download (23MB) | Preview |
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.
| Type: | Article |
|---|---|
| Title: | Loss of the crumbs cell polarity complex disrupts epigenetic transcriptional control and cell cycle progression in the developing retina |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/path.6056 |
| Publisher version: | https://doi.org/10.1002/path.6056 |
| Language: | English |
| Additional information: | © 2023 The Authors.TheJournalofPathologypublished by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.This is an open access article under the terms of theCreative Commons AttributionLicense, which permits use, distribution and reproduction in anymedium, provided the original work is properly cited. |
| Keywords: | DNA methylation, Polarity complex, RNA-seq, epigenome, iPSC, retina, transcriptome, zebrafish |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10163680 |
Archive Staff Only
 |
View Item |
