Reading LINEs within the cocaine addicted brain

Glenn A. Doyle, Tara T. Doucet-O'Hare, Matthew J. Hammond, Richard C. Crist, Adam D. Ewing, Thomas N. Ferraro, Deborah C Mash, Haig H. Kazazian, Wade H. Berrettini

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Introduction: Long interspersed element (LINE)-1 (L1) is a type of retrotransposon capable of mobilizing into new genomic locations. Often studied in Mendelian diseases or cancer, L1s may also cause somatic mutation in the developing central nervous system. Recent reports showed L1 transcription was activated in brains of cocaine-treated mice, and L1 retrotransposition was increased in cocaine-treated neuronal cell cultures. We hypothesized that the predisposition to cocaine addiction may result from inherited L1s or somatic L1 mobilization in the brain. Methods: Postmortem medial prefrontal cortex (mPFC) tissue from 30 CA and 30 control individuals was studied. An Alexafluor488-labeled NeuN antibody and fluorescence activated nuclei sorting were used to separate neuronal from non-neuronal cell nuclei. L1s and their 3' flanking sequences were amplified from neuronal and non-neuronal genomic DNA (gDNA) using L1-seq. L1 DNA libraries from the neuronal gDNA were sequenced on an Illumina HiSeq2000. Sequences aligned to the hg19 human genome build were analyzed for L1 insertions using custom "L1-seq" bioinformatics programs. Results: Previously uncataloged L1 insertions, some validated by PCR, were detected in neurons from both CA and control brain samples. Steady-state L1 mRNA levels in CA and control mPFC were also assessed. Gene ontology and pathway analyses were used to assess relationships between genes putatively disrupted by novel L1s in CA and control individuals. L1 insertions in CA samples were enriched in gene ontologies and pathways previously associated with CA. Conclusions: We conclude that neurons in the mPFC harbor L1 insertions that have the potential to influence predisposition to CA.

Original languageEnglish (US)
JournalBrain and Behavior
DOIs
StateAccepted/In press - 2017

Fingerprint

Prefrontal Cortex
Cocaine
Reading
Gene Ontology
Brain
3' Flanking Region
Neurons
Cocaine-Related Disorders
Retroelements
DNA
Human Genome
Computational Biology
Cell Nucleus
Gene Library
Central Nervous System
Cell Culture Techniques
Fluorescence
Polymerase Chain Reaction
Messenger RNA
Mutation

Keywords

  • Addiction
  • LINE1
  • Mutation
  • Neuronal development
  • Retrotransposon

ASJC Scopus subject areas

  • Behavioral Neuroscience

Cite this

Doyle, G. A., Doucet-O'Hare, T. T., Hammond, M. J., Crist, R. C., Ewing, A. D., Ferraro, T. N., ... Berrettini, W. H. (Accepted/In press). Reading LINEs within the cocaine addicted brain. Brain and Behavior. https://doi.org/10.1002/brb3.678

Reading LINEs within the cocaine addicted brain. / Doyle, Glenn A.; Doucet-O'Hare, Tara T.; Hammond, Matthew J.; Crist, Richard C.; Ewing, Adam D.; Ferraro, Thomas N.; Mash, Deborah C; Kazazian, Haig H.; Berrettini, Wade H.

In: Brain and Behavior, 2017.

Research output: Contribution to journalArticle

Doyle, GA, Doucet-O'Hare, TT, Hammond, MJ, Crist, RC, Ewing, AD, Ferraro, TN, Mash, DC, Kazazian, HH & Berrettini, WH 2017, 'Reading LINEs within the cocaine addicted brain', Brain and Behavior. https://doi.org/10.1002/brb3.678
Doyle GA, Doucet-O'Hare TT, Hammond MJ, Crist RC, Ewing AD, Ferraro TN et al. Reading LINEs within the cocaine addicted brain. Brain and Behavior. 2017. https://doi.org/10.1002/brb3.678
Doyle, Glenn A. ; Doucet-O'Hare, Tara T. ; Hammond, Matthew J. ; Crist, Richard C. ; Ewing, Adam D. ; Ferraro, Thomas N. ; Mash, Deborah C ; Kazazian, Haig H. ; Berrettini, Wade H. / Reading LINEs within the cocaine addicted brain. In: Brain and Behavior. 2017.
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AU - Crist, Richard C.

AU - Ewing, Adam D.

AU - Ferraro, Thomas N.

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AU - Kazazian, Haig H.

AU - Berrettini, Wade H.

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AB - Introduction: Long interspersed element (LINE)-1 (L1) is a type of retrotransposon capable of mobilizing into new genomic locations. Often studied in Mendelian diseases or cancer, L1s may also cause somatic mutation in the developing central nervous system. Recent reports showed L1 transcription was activated in brains of cocaine-treated mice, and L1 retrotransposition was increased in cocaine-treated neuronal cell cultures. We hypothesized that the predisposition to cocaine addiction may result from inherited L1s or somatic L1 mobilization in the brain. Methods: Postmortem medial prefrontal cortex (mPFC) tissue from 30 CA and 30 control individuals was studied. An Alexafluor488-labeled NeuN antibody and fluorescence activated nuclei sorting were used to separate neuronal from non-neuronal cell nuclei. L1s and their 3' flanking sequences were amplified from neuronal and non-neuronal genomic DNA (gDNA) using L1-seq. L1 DNA libraries from the neuronal gDNA were sequenced on an Illumina HiSeq2000. Sequences aligned to the hg19 human genome build were analyzed for L1 insertions using custom "L1-seq" bioinformatics programs. Results: Previously uncataloged L1 insertions, some validated by PCR, were detected in neurons from both CA and control brain samples. Steady-state L1 mRNA levels in CA and control mPFC were also assessed. Gene ontology and pathway analyses were used to assess relationships between genes putatively disrupted by novel L1s in CA and control individuals. L1 insertions in CA samples were enriched in gene ontologies and pathways previously associated with CA. Conclusions: We conclude that neurons in the mPFC harbor L1 insertions that have the potential to influence predisposition to CA.

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