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PLoS Comput Biol. 2017 Jun 13;13(6):e1005602. doi: 10.1371/journal.pcbi.1005602. eCollection 2017 Jun.

Histone posttranslational modifications predict specific alternative exon subtypes in mammalian brain.

Hu Q1, Kim EJ1,2, Feng J3, Grant GR4,5, Heller EA1,2,5.

Author information

1
Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, United States of America.
2
Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, United States of America.
3
Department of Biological Science, Florida State University, Tallahassee, FL, United States of America.
4
Department of Genetics, University of Pennsylvania, Philadelphia, PA, United States of America.
5
Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.

Abstract

A compelling body of literature, based on next generation chromatin immunoprecipitation and RNA sequencing of reward brain regions indicates that the regulation of the epigenetic landscape likely underlies chronic drug abuse and addiction. It is now critical to develop highly innovative computational strategies to reveal the relevant regulatory transcriptional mechanisms that may underlie neuropsychiatric disease. We have analyzed chromatin regulation of alternative splicing, which is implicated in cocaine exposure in mice. Recent literature has described chromatin-regulated alternative splicing, suggesting a novel function for drug-induced neuroepigenetic remodeling. However, the extent of the genome-wide association between particular histone modifications and alternative splicing remains unexplored. To address this, we have developed novel computational approaches to model the association between alternative splicing and histone posttranslational modifications in the nucleus accumbens (NAc), a brain reward region. Using classical statistical methods and machine learning to combine ChIP-Seq and RNA-Seq data, we found that specific histone modifications are strongly associated with various aspects of differential splicing. H3K36me3 and H3K4me1 have the strongest association with splicing indicating they play a significant role in alternative splicing in brain reward tissue.

PMID:
28609483
PMCID:
PMC5487056
DOI:
10.1371/journal.pcbi.1005602
[Indexed for MEDLINE]
Free PMC Article

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