PUBLICATION

Identification and functional study of enhancers of EYA1, the causative gene of branchio-oto-renal syndrome

Authors

Wang, F., Zhang, R., Jian, J., Sun, Y., Li, Q.

ID

ZDB-PUB-240117-2

Date

2024

Source

Developmental neuroscience 46(5): 333-340 (Journal)

Registered Authors

Li, Qiang

Keywords

none

MeSH Terms

Intracellular Signaling Peptides and Proteins*/genetics
Humans
Protein Tyrosine Phosphatases*/genetics
Protein Tyrosine Phosphatases*/metabolism
Enhancer Elements, Genetic*/genetics
Nuclear Proteins/genetics
Nuclear Proteins/metabolism
Branchio-Oto-Renal Syndrome*/genetics
Animals
Zebrafish

(all 10)

PubMed

38228108 Full text @ Dev. Neurosci.

Abstract

Introduction Branchio-oto-renal syndrome (BOR syndrome) is a rare genetic disorder with an incidence of 1 in 40,000, affecting the development of multiple organs, including the branchio, ear and kidney. It is responsible for 2% of childhood deafness. Currently, variants in the coding regions of the main causative genes, such as EYA1, SIX1, and SIX5, explain only half of the disease's etiology. Therefore, there is a need to explore the non-coding regions, which constitute the majority of the genome, especially the regulatory regions, as potential new causative factors.

Method In this study, we focused on the EYA1 gene, which accounts for over 40% of BOR syndrome cases, and conducted a screening of candidate enhancers within a 250 kb region upstream and downstream of the gene using comparative genomics. We characterized the enhancer activities of these candidates in zebrafish using the Tol2 transposon system.

Results Our findings revealed that out of the 11 conserved non-coding elements (CNEs) examined, four exhibited enhancer activity. Notably, CNE16.39 and CNE16.45 displayed tissue-specific enhancer activity in the ear. CNE16.39required the full-length 206 bp sequence for inner-ear-specific expression, while the core functional region of CNE16.45 was identified as 136 bp. Confocal microscopy results demonstrated that both CNE16.39 and CNE16.45 drove the expression of GFP in the sensory region of the crista of the inner ear in zebrafish, consistent with the expression pattern of eya1.

Conclusion This study contributes to the understanding of the regulatory network governing EYA1 expression and offers new insights to further clarify the pathogenic role of EYA1 in BOR syndrome.

Genes / Markers

Figures