Epilepsy-Associated UBE3A Deficiency Downregulates Retinoic Acid Signalling Pathway.

Meimiao Fang,Xiaobo Gao,Yali Li,Ronggui Hu,Liang Chen,Jin Ren

doi:10.3389/fgene.2021.681295

Abstract

Ubiquitin-protein ligase E3A (UBE3A) has dual functions as a E3 ubiquitin-protein ligase and coactivator of nuclear hormone receptors. Mutations or deletions of the maternally inherited UBE3A gene cause Angelman syndrome. Here, we performed transcriptome profiling in the hippocampus of Ube3am+/p+ and Ube3am–/p+ mice, and determined that the expression of the retinoic acid (RA) signalling pathway was downregulated in Ube3a-deficient mice compared to WT mice. Furthermore, we demonstrated that UBE3A directly interacts with RARα and may function as a coactivator of the nuclear receptor RARα to participate in the regulation of gene expression. Loss of UBE3A expression caused the downregulation of the expression of RA-related genes, including Erbb4, Dpysl3, Calb1, Pten, and Arhgap5 in Ube3am–/p+ mice brain tissues. This work revealed a new role for UBE3A in regulating retinoic acid (RA) signalling downstream genes and hopefully to shed light on the potential drug target of AS.

Highlights

The Ubiquitin-protein ligase E3A (UBE3A) gene is located on the proximal arm of the 15th chromosome at the q11–q13 site in humans (Kishino and Wagstaff, 1998)
A total of 886 genes were screened with the threshold of significance at P < 0.05 and foldchange > 1.2, among which 463 genes were up-regulated and 423 genes were down-regulated in the Ube3am−/p+ group compared to WT control group, shown in volcano plot (Figure 1A and Supplementary Table 2)
We found that 28 retinoic acid (RA)-targeted genes are differentially expressed in Ube3am−/p+ male mice compared to WT male mice (Figure 1B)

Summary

Introduction

The UBE3A ( known as E6AP) gene is located on the proximal arm of the 15th chromosome at the q11–q13 site in humans (Kishino and Wagstaff, 1998). UBE3A exerts two independent functions in vivo, with the HECT domain mainly functioning as a ubiquitin ligase, with LxxLL motif as a nuclear receptor coactivator (Khan et al, 2006; Wang et al, 2017). The LxxLL motif is a highly conserved signature sequence that binds nuclear receptors to activate gene expression. UBE3A is biallelically expressed in most tissues except nerve tissues, where it is imprinted with maternal allelic expression (Yamasaki et al, 2003). UBE3A is expressed only from the maternal allele, while the paternal allele is epigenetically silent (paternal imprinting) (Albrecht et al, 1997). Researchers have identified loss-of-function mutations of maternal UBE3A in 8% Angelman syndrome (AS) cases (Maranga et al, 2020). The behavioural characteristics of AS include intellectual disability, seizures, short attention span, excessive exercise behaviour, sleep disturbance, happy disposition and fascination with water (Williams et al, 2006; Tan et al, 2011; Gu et al, 2019)

Methods

Results

Conclusion