Histone posttranslational modifications predict specific alternative exon subtypes in mammalian brain

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

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.

MeSH terms

  • Animals
  • Brain / physiopathology*
  • Cocaine-Related Disorders / genetics*
  • Computer Simulation
  • Exons / genetics*
  • Histones / genetics*
  • Mice
  • Models, Genetic
  • Nerve Tissue Proteins / genetics
  • Protein Processing, Post-Translational / genetics*
  • RNA Splice Sites / genetics*

Substances

  • Histones
  • Nerve Tissue Proteins
  • RNA Splice Sites

Grant support

Funding for this work was provided by The Perelman School of Medicine (EAH), The Charles E Kaufman Foundation (Grant KA2016_85225 to EAH), The Whitehall Foundation (Grant 2016-12-33 to EAH), and The National Center for Advancing Translational Sciences (5UL1TR000003, GRG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.