Aberrant splicing as the cause of Rubinstein-Taybi syndrome

Rubinstein-Taybi syndrome is a genetic condition characterized by moderate to severe learning difficulties, distinctive facial features and distal limb abnormalities. These characteristics are caused by a heterozygous mutation or deletion in the CREBBP and/or EP300 gene. These two genes encode paralogs that act as lysine acetyltransferases involved in transcriptional regulation and chromatin remodeling. Our recent work described the important role of EP300 as a pre-mRNA splicing regulator. We have shown that EP300 acetylates splicing factors, in addition to histones, to change their RNA binding characteristics. Here we study whether EP300’s role as a splicing regulator promotes the aberrant splicing that triggers Rubinstein-Taybi syndrome. Analyzing RNA-seq results of cells silenced for EP300, we identified EP300 targets that have a role in neurodevelopment. A specific target we plan to study is the histone methyltransferase EHMT1, known to be important in neurodevelopment. Our results indicate that EP300 regulates EHMT1 exon 11. To understand the importance of EHMT1 isoforms, we will generate a neuronal cell line expressing only the short isoform and will monitor neuronal differentiation. Until now research has focused on EP300’s role as a transcription regulator; here we expect to uncover the importance of EP300’s splicing target EHMT1 and study its role in promoting Rubinstein-Taybi syndrome.