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Elife. 2016 Feb 19;5. pii: e10421. doi: 10.7554/eLife.10421.

Regulatory consequences of neuronal ELAV-like protein binding to coding and non-coding RNAs in human brain.

Author information

1
Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States.
2
Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
3
Seaver Autism Center for Research and Treatment, New York, United States.
4
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, United States.
5
New York Genome Center, New York, United States.
6
Department of Pharmacology and Systems Therapeutics, BD2K-LINCS Data Integration and Coordination Center, Mount Sinai Knowledge Management Center for Illuminating the Druggable Genome, Icahn School of Medicine at Mount Sinai, New York, United States.
7
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, United States.
8
James J. Peters VA Medical Center, New York, United States.
9
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, United States.
10
Mindich Child Health Institute, Icahn School of Medicine at Mount Sinai, New York, United States.
11
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United States.

Abstract

Neuronal ELAV-like (nELAVL) RNA binding proteins have been linked to numerous neurological disorders. We performed crosslinking-immunoprecipitation and RNAseq on human brain, and identified nELAVL binding sites on 8681 transcripts. Using knockout mice and RNAi in human neuroblastoma cells, we showed that nELAVL intronic and 3' UTR binding regulates human RNA splicing and abundance. We validated hundreds of nELAVL targets among which were important neuronal and disease-associated transcripts, including Alzheimer's disease (AD) transcripts. We therefore investigated RNA regulation in AD brain, and observed differential splicing of 150 transcripts, which in some cases correlated with differential nELAVL binding. Unexpectedly, the most significant change of nELAVL binding was evident on non-coding Y RNAs. nELAVL/Y RNA complexes were specifically remodeled in AD and after acute UV stress in neuroblastoma cells. We propose that the increased nELAVL/Y RNA association during stress may lead to nELAVL sequestration, redistribution of nELAVL target binding, and altered neuronal RNA splicing.

KEYWORDS:

Y RNA; alternative splicing; alzheimer's disease; biochemistry; human; imr-32 cells; mRNA stability; mouse; nELAVL; neuronal RNA binding protein; neuroscience; noncoding RNA

PMID:
26894958
PMCID:
PMC4798961
DOI:
10.7554/eLife.10421
[Indexed for MEDLINE]
Free PMC Article

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