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Post-transcriptional remodelling is temporally deregulated during motor neurogenesis in human ALS models

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE98290 | GEO | 2017/05/31

SECONDARY ACCESSION(S): PRJNA384592

REPOSITORIES: GEO

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Post-transcriptional remodelling is temporally deregulated during motor neurogenesis in human ALS models

Project description:Mutations causing amyotrophic lateral sclerosis (ALS) strongly implicate regulators of RNA-processing that are ubiquitously expressed throughout development. To understand the molecular impact of ALS-causing mutations on early neuronal development and disease, we performed transcriptomic analysis of differentiated human control and VCP-mutant induced pluripotent stem cells (iPSCs) during motor neurogenesis. We identify intron retention (IR) as the predominant splicing change affecting early stages of wild-type neural differentiation, targeting key genes involved in the splicing machinery. Importantly, IR occurs prematurely in VCP-mutant cultures compared with control counterparts; these events are also observed in independent RNAseq datasets from SOD1- and FUS-mutant motor neurons (MNs). Together with related effects on 3’UTR length variation, these findings implicate alternative RNA-processing in regulating distinct stages of lineage restriction from iPSCs to MNs, and reveal a temporal deregulation of such processing by ALS mutations. Thus, ALS-causing mutations perturb the same post-transcriptional mechanisms that underlie human motor neurogenesis.

2018-03-08 | GSE98289 | GEO