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| Status |
Public on Mar 01, 2020 |
| Title |
Imprinting effects of UBE3A loss on synaptic gene networks and Wnt signaling pathways |
| Organism |
Rattus norvegicus |
| Experiment type |
Expression profiling by high throughput sequencing
Methylation profiling by high throughput sequencing
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| Summary |
UBE3A encodes a E3 ubiquitin ligase whose loss from the maternal allele causes the neurodevelopmental disorder Angelman syndrome. Previous studies of UBE3A function have not examined full Ube3a deletion in mouse, the complexity of imprinted gene networks in brain, nor the molecular basis of systems-level cognitive dysfunctions in Angelman syndrome. We therefore utilized a systems biology approach to elucidate how UBE3A loss impacts the early postnatal brain in a novel CRISPR/Cas9 engineered rat Angelman model of a complete Ube3a deletion. Strand-specific transcriptome analysis of offspring from maternally or paternally inherited Ube3a deletions revealed the expected parental expression patterns of Ube3a sense and antisense transcripts by postnatal day 2 (P2) in hypothalamus and day 9 (P9) in cortex, compared to wild-type littermates. The dependency of genome-wide effects on parent-of-origin, Ube3a genotype, and time (P2, P9) was investigated through transcriptome (RNA-seq of cortex and hypothalamus) and methylome (whole genome bisulfite sequencing of hypothalamus). Weighted gene co-expression and co-methylation network analyses identified co-regulated networks in maternally inherited Ube3a deletion offspring enriched in postnatal developmental processes including Wnt signaling, synaptic regulation, neuronal and glial functions, epigenetic regulation, ubiquitin, circadian entrainment, and splicing. Furthermore, we showed that loss of the paternal Ube3a antisense transcript resulted in both unique and overlapping dysregulated gene pathways with maternal loss, predominantly at the level of differential methylation. Together, these results provide a holistic examination of the molecular impacts of UBE3A loss in brain, supporting the existence of interactive epigenetic networks between maternal and paternal transcripts at the Ube3a locus.
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| Overall design |
Hypothalamus and cortex from P2 and P9 female rat pups in triplicate each with maternal and paternal-derived UBE3A deletion and litter-matched controls. RNA and DNA were extracted from the same sample in hypothalamus.
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| Contributor(s) |
Lopez SJ, Segal DJ, LaSalle JM |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Sep 10, 2019 |
| Last update date |
Mar 01, 2020 |
| Contact name |
Simon Jesse Lopez |
| E-mail(s) |
sjlop@ucdavis.edu
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| Phone |
5307547840
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| Organization name |
UC Davis
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| Department |
MMI
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| Lab |
LaSalle
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| Street address |
One Shields Ave
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| City |
Davis |
| State/province |
CA |
| ZIP/Postal code |
95616 |
| Country |
USA |
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| Platforms (2) |
| GPL22396 |
Illumina HiSeq 4000 (Rattus norvegicus) |
| GPL24688 |
HiSeq X Ten (Rattus norvegicus) |
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| Samples (72)
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| Relations |
| BioProject |
PRJNA564819 |
| SRA |
SRP221276 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE137217_DMRs.xlsx |
939.6 Kb |
(ftp)(http) |
XLSX |
| GSE137217_control_background_smoothed_methylation.txt.gz |
2.4 Mb |
(ftp)(http) |
TXT |
| GSE137217_cortex_counts.txt.gz |
1.4 Mb |
(ftp)(http) |
TXT |
| GSE137217_hypothalamus_counts.txt.gz |
1.3 Mb |
(ftp)(http) |
TXT |
| GSE137217_maternal_background_smoothed_methylation.txt.gz |
2.7 Mb |
(ftp)(http) |
TXT |
| GSE137217_paternal_background_smoothed_methylation.txt.gz |
2.1 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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