Genomics

Dataset Information

161

SMN deficiency in spinal muscular atrophy causes widespread intron retention and DNA damage


ABSTRACT: Spinal muscular atrophy is the leading genetic cause of infant mortality and is caused by homozygous loss of the SMN1 gene. We investigated global transcriptome changes in the spinal cord of inducible SMA mice. SMN depletion caused widespread retention of introns with weak splice sites or belonging to the minor (U12) class. We further demonstrated accumulation of DNA double strand breaks in the spinal cord of SMA mice and in human SMA cell culture models. DNA damage was partially rescued by suppressing the formation of R-loops, which accumulated over retained introns. We propose that instead of single gene effects, pervasive splicing defects caused by SMN deficiency trigger a global DNA damage and stress response, thus compromising motor neuron survival. Overall design: mRNA-seq: Total spinal cord from SMA and Control mice (rescue experiment) at d20 and d30; human SH-SY5Y cells expressing SMN or Control shRNA for 7d; human iPSC-derived motor neurons expressing SMN or Control shRNA for 5d; total spinal cord from SMA and Control mice (induction experiment) at d10, d20, and d30. DRIP-seq: SH-SY5Y cells expressing SMN or Control shRNA for 7d and immunoprecipitated with S9.6 antibody targeting RNA:DNA hybrids.

INSTRUMENT(S): Illumina HiSeq 2000 (Homo sapiens)

SUBMITTER: John Carulli 

PROVIDER: GSE87281 | GEO | 2017-03-21

SECONDARY ACCESSION(S): PRJNA343962

REPOSITORIES: GEO

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Publications

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage.

Jangi Mohini M   Fleet Christina C   Cullen Patrick P   Gupta Shipra V SV   Mekhoubad Shila S   Chiao Eric E   Allaire Norm N   Bennett C Frank CF   Rigo Frank F   Krainer Adrian R AR   Hurt Jessica A JA   Carulli John P JP   Staropoli John F JF  

Proceedings of the National Academy of Sciences of the United States of America 20170307 12


Spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease, is the leading monogenic cause of infant mortality. Homozygous loss of the gene survival of motor neuron 1 (SMN1) causes the selective degeneration of lower motor neurons and subsequent atrophy of proximal skeletal muscles. The SMN1 protein product, survival of motor neuron (SMN), is ubiquitously expressed and is a key factor in the assembly of the core splicing machinery. The molecular mechanisms by which disruption of  ...[more]

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