MeCP2 gates spatial learning-induced alternative splicing events in the mouse hippocampus
- PDF / 4,157,864 Bytes
- 16 Pages / 595.276 x 790.866 pts Page_size
- 77 Downloads / 177 Views
Open Access
RESEARCH
MeCP2 gates spatial learning‑induced alternative splicing events in the mouse hippocampus David V. C. Brito1 , Kubra Gulmez Karaca1,3,4† , Janina Kupke1† , Lukas Frank2 and Ana M. M. Oliveira1*
Abstract Long-term memory formation is supported by functional and structural changes of neuronal networks, which rely on de novo gene transcription and protein synthesis. The modulation of the neuronal transcriptome in response to learning depends on transcriptional and post-transcriptional mechanisms. DNA methylation writers and readers regulate the activity-dependent genomic program required for memory consolidation. The most abundant DNA methylation reader, the Methyl CpG binding domain protein 2 (MeCP2), has been shown to regulate alternative splicing, but whether it establishes splicing events important for memory consolidation has not been investigated. In this study, we identified the alternative splicing profile of the mouse hippocampus in basal conditions and after a spatial learning experience, and investigated the requirement of MeCP2 for these processes. We observed that spatial learning triggers a wide-range of alternative splicing events in transcripts associated with structural and functional remodeling and that virus-mediated knockdown of MeCP2 impairs learning-dependent post-transcriptional responses of mature hippocampal neurons. Furthermore, we found that MeCP2 preferentially affected the splicing modalities intron retention and exon skipping and guided the alternative splicing of distinct set of genes in baseline conditions and after learning. Lastly, comparative analysis of the MeCP2-regulated transcriptome with the alternatively spliced mRNA pool, revealed that MeCP2 disruption alters the relative abundance of alternatively spliced isoforms without affecting the overall mRNA levels. Taken together, our findings reveal that adult hippocampal MeCP2 is required to finetune alternative splicing events in basal conditions, as well as in response to spatial learning. This study provides new insight into how MeCP2 regulates brain function, particularly cognitive abilities, and sheds light onto the pathophysiological mechanisms of Rett syndrome, that is characterized by intellectual disability and caused by mutations in the Mecp2 gene. Keywords: Alternative splicing, Adult brain, DNA methylation, Gene transcription, Rett syndrome, RNA sequencing Introduction It is well established that long-term memory formation requires de novo gene transcription and protein synthesis. In response to neuronal activity, immediate early *Correspondence: [email protected]‑heidelberg.de † Kubra Gulmez Karaca and Janina Kupke equally contributed to this work 1 Department of Neurobiology, Interdisciplinary Centre for Neurosciences (IZN), Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany Full list of author information is available at the end of the article
genes are rapidly transcribed, many of which initiate a second, delayed wave of gene transcription [1]. These newly synthesi
Data Loading...
