Epilepsy-Associated UBE3A Deficiency Downregulates Retinoic Acid Signalling Pathway

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.

Shared and divergent contribution of vitamin A and oxytocin to the aetiology of autism spectrum disorder

“…NSD1 was highly connected with ASD core genes; it carried two functional DNMs and two pathogenic dn CNVs in patients with ASD, but only one functional DNM in controls. UBE3A and NSD1 reportedly function as coactivators that interact with RAR to regulate gene transcription [73] , [74] . Notably, NCOA6 (nuclear receptor coactivator 6), a potential new VA-related risk gene for ASD, carries two recurrent stop-gain DNMs (p.R303X) in patients with ASD and is connected to 37 PC-ASD core genes.…”

The Contribution of Hippocampal All-Trans Retinoic Acid (ATRA) Deficiency to Alzheimer’s Disease: A Narrative Overview of ATRA-Dependent Gene Expression in Post-Mortem Hippocampal Tissue

“…This data set contains a heterogeneous population of AD hippocampal tissue samples that included both sexes and multiple APOE genotypes [107]. We examined genes known to possess RAREs and/or known to be transcriptionally controlled by ATRA (the VA transcriptome) [108][109][110][111], which included 297 genes that were shown to possess RARβ binding sites [112]. In addition, we also consulted the web-accessible transcription factor databases TF2DNA [113] and Enrichr [114][115][116] for ATRA-sensitive genes and ATRA-related transcription factors.…”

“…RBP1 (frequently designated CRBP1), the intracellular retinol carrier that accepts retinol from the STRA6 transporter [20], was also found to be transcriptionally downregulated in the hippocampus of AD brains (Table 1). Both RBP1 and RBP4 are known to be transcriptionally regulated by ATRA [108,110,111,117,118]. Retinol dehydrogenase 12 (RDH12) is one of the major cytoplasmic enzymes used in the conversion of retinol to retinal and was significantly downregulated.…”

Identification of key biomarkers in Angelman syndrome by a multi-cohort analysis

“…There is an estimated incidence of AS between 1/10,000 and 1/20,000 ( 2 ). Mutations of the maternal UBE3A (ubiquitin protein ligase E3A) gene cause AS in 8% of the cases ( 3 , 4 ). UBE3A affects protein levels and function through ubiquitination.…”