Imprinting effects of UBE3A loss on synaptic gene networks and Wnt signaling pathways
| Autor: | David J. Segal, Benjamin I. Laufer, S. Jesse Lopez, Henriette O'Geen, Jill L. Silverman, Janine M. LaSalle, Ulrika Beitnere, Elizabeth L. Berg |
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| Rok vydání: | 2019 |
| Předmět: |
Bisulfite sequencing
Gene Expression Reproductive health and childbirth Medical and Health Sciences Epigenesis Genetic Transcriptome Rats Sprague-Dawley 0302 clinical medicine Gene Regulatory Networks Wnt Signaling Pathway Genetics (clinical) Pediatric Genetics & Heredity Cerebral Cortex Neurons 0303 health sciences Systems Biology Brain General Medicine Biological Sciences Cell biology Ubiquitin ligase Neurological DNA methylation Female Neuroglia Biotechnology congenital hereditary and neonatal diseases and abnormalities Intellectual and Developmental Disabilities (IDD) Ubiquitin-Protein Ligases Hypothalamus Biology Article 03 medical and health sciences Genomic Imprinting Rare Diseases Genetic Angelman syndrome Genetics UBE3A medicine Animals Epigenetics Intellectual and Developmental Disabilities Molecular Biology 030304 developmental biology Gene Expression Profiling Human Genome Neurosciences medicine.disease Brain Disorders Rats Synapses biology.protein Sprague-Dawley Angelman Syndrome Genomic imprinting 030217 neurology & neurosurgery Epigenesis |
| Zdroj: | Hum Mol Genet Human molecular genetics, vol 28, iss 22 |
| ISSN: | 1460-2083 |
| Popis: | Ubiquitin E3 ligase 3A (UBE3A) encodes an E3 ubiquitin ligase whose loss from the maternal allele causes the neurodevelopmental disorder Angelman syndrome (AS). 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 AS. 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 and P9) was investigated through transcriptome (RNA sequencing 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. |
| Databáze: | OpenAIRE |
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