Stochastic Principles Governing Alternative Splicing of RNA
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE80016 | GEO | 2017/09/07
SECONDARY ACCESSION(S): PRJNA317639
REPOSITORIES: GEO
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Project description:DNA methylation, in concert with other epigenetic regulators, controls the accessibility of transcription factors to DNA. While comprehensively described in the development of neuronal progenitors, the role of DNA methylation/demethylation in neuronal lineage/subtype specification is not known. By profiling two distinct neuronal lineages, and five neuron subtypes in the hippocampus and striatum, we uncovered a set of five principles that govern DNA methylation dynamics in neurodevelopment. By dividing neurodevelopment to three alternating methylation and demethylation periods and applying the principles to each of these stages, we created a matrix that comprehensively describes the targets, genomic contexts, functional consequences and putative mechanisms of methylation/demethylation events. The overarching theme is that the developmental methylation program is remarkably similar in the hippocampal and striatal lineages, with significant divergence only occurring during subtype specification. Our matrix can be cross-referenced with disease-associated epigenetic changes to specify the possible events and underlying principles compromised in disease.
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Project description:Background: RNA silencing pathways play critical roles in gene regulation, virus infection, and transposon control. RNA interference (RNAi) is mediated by small interfering RNAs (siRNAs), which are liberated from double stranded (ds) RNA precursors by Dicer and direct the RNA-induced silencing complex (RISC) to target transcripts. Recent efforts have uncovered important principles governing small RNA (smRNA) sorting into RISC, yet mechanisms defining substrate selection by Dicer proteins remain uncharacterized. Methodology: To better characterize Dicer-2 substrates in Drosophila, we examined the antiviral RNAi response, which generates virus-derived siRNAs from viral RNA. Using high-throughput sequencing, we found that diverse viruses were uniquely targeted; substrates included dsRNA replication intermediates and intramolecular RNA stem loops. smRNA distribution patterns from viral and synthetic dsRNA precursors were highly reproducible, and machine learning techniques identified characteristics of precursor molecules and smRNA duplexes important in determining relative smRNA abundance. Significance: To our knowledge, this study provides the first description of the rules governing Dicer-2 substrate selection, which has important implications for exogenous RNA silencing technologies and the development of smRNA-based antiviral therapeutics. virus-derived siRNA (vsiRNA) expression comparison between control and 4 different virus-infected cells in control as well as 5 different RNAi pathway protein knock-downs in Drosophila dl1 cells
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