RBFOX2 regulated EYA3 isoforms partner with SIX4 or ZBTB1 to control transcription during myogenesis

Hannah J Wiedner; R Eric Blue; Matheus Sadovsky; C Allie Mills; Xander H T Wehrens; Laura E Herring; Jimena Giudice

doi:10.1016/j.isci.2023.108258

RBFOX2 regulated EYA3 isoforms partner with SIX4 or ZBTB1 to control transcription during myogenesis

iScience. 2023 Oct 20;26(11):108258. doi: 10.1016/j.isci.2023.108258. eCollection 2023 Nov 17.

Authors

Hannah J Wiedner^{1

2}, R Eric Blue¹, Matheus Sadovsky¹, C Allie Mills³, Xander H T Wehrens⁴, Laura E Herring³, Jimena Giudice^{1

2

5}

Affiliations

¹ Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
² Curriculum in Genetics and Molecular Biology (GMB), The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³ UNC Proteomics Core Facility, Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA.
⁵ McAllister Heart Institute, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Abstract

Alternative splicing is a prevalent gene-regulatory mechanism, with over 95% of multi-exon human genes estimated to be alternatively spliced. Here, we describe a tissue-specific, developmentally regulated, highly conserved, and disease-associated alternative splicing event in exon 7 of the eyes absent homolog 3 (Eya3) gene. We discovered that EYA3 expression is vital to the proliferation and differentiation of myoblasts. Genome-wide transcriptomic analysis and mass spectrometry-based proteomic studies identified SIX homeobox 4 (SIX4) and zinc finger and BTB-domain containing 1 (ZBTB1), as major transcription factors that interact with EYA3 to dictate gene expression. EYA3 isoforms differentially regulate transcription, indicating that splicing aids in temporal control of gene expression during muscle cell differentiation. Finally, we identified RNA-binding fox-1 homolog 2 (RBFOX2) as the main regulator of EYA3 splicing. Together, our findings illustrate the interplay between alternative splicing and transcription during myogenesis.

Keywords: Molecular biology; Omics; Physiology.

Abstract

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