SFRS7-Mediated Splicing of Tau Exon 10 Is Directly Regulated by STOX1A in Glial Cells

Daan Van Abel,Dennis R Hölzel,Shushant Jain,Yama W L Zheng,Rossa W K Chiu,Eric Z Chen,Marie Van Dijk,Cees B M Oudejans,Hao Sun,Fiona M F Lun,Y M Dennis Lo

doi:10.1371/journal.pone.0021994

Daan Van Abel, Dennis R Hölzel + Show 9 more

Open Access

https://doi.org/10.1371/journal.pone.0021994

Copy DOI

Abstract

BackgroundIn this study, we performed a genome-wide search for effector genes bound by STOX1A, a winged helix transcription factor recently demonstrated to be involved in late onset Alzheimer's disease and affecting the amyloid processing pathway.Methodology/Principal FindingsOur results show that out of 218 genes bound by STOX1A as identified by chromatin-immunoprecipitation followed by sequencing (ChIP-Seq), the serine/arginine-rich splicing factor 7 (SFRS7) was found to be induced, both at the mRNA and protein levels, by STOX1A after stable transfection in glial cells. The increase in SFRS7 was followed by an increase in the 4R/3R ratios of the microtubule-associated protein tau (MAPT) by differential exon 10 splicing. Secondly, STOX1A also induced expression of total tau both at the mRNA and protein levels. Upregulation of total tau expression (SFRS7-independent) and tau exon 10 splicing (SFRS7-dependent), as shown in this study to be both affected by STOX1A, is known to have implications in neurodegeneration.ConclusionsOur data further supports the functional importance and central role of STOX1A in neurodegeneration.

Highlights

Storkhead box 1 (STOX1A), a transcription factor structurally and functionally related to the forkhead family of transcription factors, characterized by a 100 amino acid DNA-binding motif termed the winged helix domain, was recently found to be a susceptibility gene for pre-eclampsia [1,2], a hypertensive disorder of pregnancy which remains a major cause of maternal and perinatal mortality and morbidity [3]
High throughput sequencing identifies a STOX1A DNA binding region in the promoter of SFRS7, a gene involved in the splicing of tau exon 10
Using a genome-wide, antibody-independent approach, 218 genomic regions were found to be bound by STOX1A in SK-NSH cells (Dataset S1)

Summary

Introduction

Storkhead box 1 (STOX1A), a transcription factor structurally and functionally related to the forkhead family of transcription factors, characterized by a 100 amino acid DNA-binding motif termed the winged helix domain, was recently found to be a susceptibility gene for pre-eclampsia [1,2], a hypertensive disorder of pregnancy which remains a major cause of maternal and perinatal mortality and morbidity [3]. STOX1A was found to be functionally involved in late-onset Alzheimer’s disease (LOAD) [4], a progressive neurodegenerative disease of the brain which is characterized by memory loss and impaired visiospatial skills involving elderly patients (.65 years) of both sexes [6]. Van Dijk and co-workers showed that STOX1A is expressed abundantly in the brain, correlates with the severity of late onset Alzheimer’s disease (LOAD) and transactivates the leucine-rich repeat transmembrane 3 (LRRTM3) gene [4]. We performed a genome-wide search for effector genes bound by STOX1A, a winged helix transcription factor recently demonstrated to be involved in late onset Alzheimer’s disease and affecting the amyloid processing pathway

Objectives

Methods

Results

Conclusion